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Monteiro, Vasconcelos Ines [Verfasser]. "Epigenetic quantification of tumor-infiltrating T-lymphocytes in epithelial ovarian tumors / Ines Monteiro Vasconcelos." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/1052529828/34.
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Schlecker, Eva [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "The role of tumor-infiltrating MDSC subsets in tumor progression / Eva Schlecker ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2011. http://d-nb.info/1179229649/34.
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Kurt, Robert Anthony 1968. "Characterization of T lymphocytes infiltrating sites of tumor progression and regression during concomitant tumor immunity." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282126.
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The cellular infiltration of solid tumors is indicative of an immune response to cancerous growths. Unfortunately, most tumors grow progressively despite this infiltration. Therefore, the infiltrate from a regressing tumor is necessary in order to examine the requirements for tumor rejection. Due to the rarity of tumor rejection, elucidating the requirements is difficult without an animal model. The sponge model of concomitant tumor immunity allowed the examination of the components associated with tumor rejection. In the model of concomitant tumor immunity an animal is given a primary tumor followed by a secondary tumor challenge. Despite the progression of the primary tumor, the secondary tumor challenge is rejected. In this model the secondary tumor challenge is delivered into a preimplanted gelatin sponge matrix which can be retrieved in order to capture the components associated with tumor rejection. Retrieval of both the primary progressing tumor and the gelatin sponge allowed a direct comparison of the factors associated with tumor progression and rejection. Using this model, we have examined the progressing and rejected tumor sites for differences in T cell cytotoxicity, V beta T cell receptor usage, and the expression of cytokine genes and signal transducing proteins. The results from this study demonstrated that the T cells isolated from progressing tumor sites were not cytolytic, whereas the T cells from the rejection sites showed significant cytolysis towards the autologous tumor cells in vitro. Surprisingly, the T cell infiltration into the progressing and rejected tumor sites were similar with V beta 1 and V beta 8 T cell receptor bearing T cells predominating at both locations. The T cell response also showed clonal restriction upon examination of the complementarity determining region 3 (CDR3) of the T cell receptor. Significantly, the rejection site showed higher gene expression levels of IFN-γ, TNF-α, IL-2, IL-4, IL-10, and IL-12 and reduced TGF-β gene expression compared to the progressing tumor site. Finally, although the T cells from the progressing tumor site showed an altered pattern of tyrosine phosphorylation, the signaling molecules p59ᶠʸⁿ and CD3 ζ were expressed at comparable levels in the T cells from both sites. These data strongly suggest that the tumor microenvironment may play a major role in orchestrating an anti-tumor immune response.
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Morgan, Clifford Grant. "Characterization of Tumor Infiltrating Lymphocytes in Pediatric Cancers and the Development of Novel Immunotherapies." Thesis, The George Washington University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3705722.
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Cytotoxic T lymphocytes (CTLs) are the primary component of the adaptive immune system responsible for clearance of virally infected and tumorigenic cells. In cancer however, this tumor-specific immune response is often impaired. The impairment is multifactorial; some cancers utilize mechanisms to evade the immune system through downregulation of Major Histocompatability Complex I or lack of tumor-specific antigens, while others use methods to actively inhibit local function of tumor-induced immune responses via production of immunosuppressive cytokines, Fas-mediated apoptosis, or recruitment of T regulatory cells (Tregs). These Tregs function to further immune regulate and inhibit CTLs, using methods such as suppressive cytokines, and cytotoxic killing. All of these components lead to an “on/off” phenotype, where CTL effector function is shut down within the Tumor Immunosuppressive Microenvironment (TIM), but can be recovered quickly upon removal of CTLs from the TIM. The transient impairment of Tumor Infiltrating Lymphocytes (TIL) has been described in mouse models, but is poorly characterized in humans.
In this dissertation, we examined infiltration of CTLs across several types of human pediatric cancers, taken from patients who had not undergone prior treatment. We found tumors associated with favorable prognoses, including Wilms’ Tumor and Neuroblastoma (NB), had higher levels of CTL infiltration than those with less favorable prognoses, e.g. Ependymoma, which possessed no observable infiltration. Additionally, we demonstrate the TIL “on/off” phenotype in a case of Pilocytic Astrocytoma, demonstrating significant recovery of TIL effector function.
We proposed that the poor infiltration and impaired effector function in these pediatric tumors was a direct result of the TIM, and sought to improve this immune response by developing an attenuated live cell vaccine, utilizing a murine NB model, Neuro2a, to create a NB line with knock down (KD) of Inhibitor of Differentiation 2 (Id2), which impaired their ability to form tumors in vivo. In prophylactic and therapeutic models, introduction of Id2-KD cells in combination with the immune checkpoint blockade inhibitor anti-CTLA-4, induced an increase in CTLs capable of homing to the tumor, that were also able to employ effector function within the TIM, resulting in clearance of wild-type Neuro2a tumors.
A separate emerging immunotherapeutic approach is to express a Chimeric Antigen Receptor (CAR) on CTLs that allows them to be activated to kill cells expressing the CAR-specific protein, bypassing MHC presentation. Using a murine Rhabdomyosarcoma model, we demonstrate that tumor infiltrating Tregs express lytic molecules, encouraging us to develop a method of successfully transducing Tregs with a CAR (DC101), rather than CTLs, thereby exploiting characteristics of the Treg in the TIM, specifically their cytotoxic capability and their unique recruitment and ability to thrive in that environment. We demonstrate in vitro CAR-mediated redirection of lytic effector function using DC101-expressing CTLs against tumor cell lines, though attempting to increase Treg cytotoxicity in vitro via known inducers of CTL cytotoxicity (IFNα or IL-12) or known inducers of Tregs within the TIM (TGF-β1) showed no increase in Treg cytotoxicity.
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Rieger, Jan Hendrik [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Targets of tumor infiltrating lymphocyte reactivity in pancreatic cancer / Jan Hendrik Rieger ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1199611484/34.
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Ko, Kuibeom. "Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3[+]CD25[+]CD4[+] regulatory T cells." Kyoto University, 2006. http://hdl.handle.net/2433/135631.
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Hansmann, Leo Alexander [Verfasser]. "A single cell approach to tumor-infiltrating lymphocytes in solid and hematopoietic malignancies / Leo Alexander Hansmann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1200409574/34.
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Ito, Takeshi. "The therapeutic potential of multiclonal tumoricidal T cells derived from tumor infiltrating lymphocyte-derived iPS cells." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/265194.
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Zhang, Hua. "A human monoclonal anti-melanoma single chain Fv (scFv) antibody derived from tumor-infiltrating B lymphocytes." Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187293.
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The development of recombinant DNA technology has made it feasible to clone, construct and express fully human immunoglobulin molecules. Here we report a novel methodology to make human antitumor scFv antibodies from tumor-infiltrating B lymphocytes (TIL-B). We isolated and expanded TIL-B from melanomas in the presence of EBV. The transformed B cells secreting tumor-specific antibodies were identified and cloned by limiting dilution. From one B cell clone with specific melanoma reactivity, we captured the immunoglobulin variable region genes, V(H) and V(k), by polymerase chain reaction (peR), sequenced the genes and linked them together by peR assembly using a (Gly₄Ser)₃ linker to form the scFv gene that was subsequently cloned into the pET21d vector and expressed. The scFv protein, obtained, with a molecular weight of 29 KD was purified and biotinylated for further characterization. The scFv demonstrated specific tumor reactivity to 21 of 24 different melanoma cell lines and not to 14 non-melanoma tumor cell lines, including breast, ovarian and colon cancer cell lines, normal human melanocytes as well as normal human leukocytes. These results were obtained using 1) a tumor cell ELISA, 2) fixed cell immunofluorescence and 3) live cell flow cytometry. The immunoprecipitation results indicated that a protein antigen of 45 KD was recognized by the scFv. Since we previously reported that about 70% of human tumors of different histologic types contain tumor-infiltrating B lymphocytes producing specific anti-tumor antibodies, this approach offers a rapid. effective method by combining in vitro B cell expansion and peR-gene cloning to elucidate the repertoire of the human anti-tumor immune responses and to make human monoclonal anti-tumor antibody molecules.
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Schnappinger, Julia [Verfasser], and Elfriede [Akademischer Betreuer] Nößner. "Profiling human tumor infiltrating leukocytes comparing renal cell and hepatocellular carcinoma / Julia Schnappinger ; Betreuer: Elfriede Nößner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1225682452/34.
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Ng, Bernice Yu Jing. "Chronic Inflammation-Driven Tumor Promotion Asociated with CD8+ T Cells." Yale University, 2008. http://ymtdl.med.yale.edu/theses/available/etd-08232007-122524/.
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Chronic inflammation is associated with carcinoma development in several clinical settings, and we sought to investigate the role of T cells in this phenomenon using the DMBA/TPA two-stage chemical carcinogenesis protocol. We demonstrate that, paradoxical to models of immunosurveillance, wild-type (WT) mice have a markedly higher rate of tumor formation relative to strains lacking CD8+ T cells. Adoptive transfers of antibody-coated magnetic bead-enriched peripheral CD8+ T cells into TCRáâ-/- mice confirmed that the increased mean tumor area and progression to carcinoma was attributable to the presence of CD8+ T cells. All analyzed strains of mice in which the CD8 compartment was intact (WT, CD4-/-) showed significant increases in tumor susceptibility. Putative tumor-promoting (T-pro) cells (TCRáâ+CD8+CD44+CD62L- tumor infiltrating lymphocytes, TILs) were directly compared to their phenotypic equivalents in peripheral blood lymphocytes (PBLs). In WT and CD4-deficient mice, CD8+ TILs consistently revealed a markedly higher relative expression, by RT-PCR, of IFNã, TNFá and COX-2, and a striking decrease in expression of perforin. Cytokine-bead analysis (CBA) comparison of CD8+ and CD4+ TIL in tumors from WT mice confirmed the increased expression by the CD8+ TIL of IFNã and TNFá. To our knowledge, this is the first demonstration of increased carcinogenesis attributable to CD8+ TILs, characterized by their high IFNã, TNFá, and COX-2 production and defective perforin production relative to phenotypically equivalent PBLs. These studies may have mechanistic implications for the role of T cells in inflammation-associated carcinogenesis.
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Verdonck, Magali. "FTIR imaging: a potential new tool to characterize cancer cells and tumor infiltrating lymphocytes in human breast cancer." Doctoral thesis, Universite Libre de Bruxelles, 2015. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209047.
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Breast cancer is the most common cancer in women. It is a highly heterogeneous disease in terms of histology, therapeutic response and patient outcomes. Early and accurate detection of breast cancer is crucial as the patient prognosis varies greatly depending on the diagnosis of the disease. Nonetheless current breast cancer classification methods fail to precisely sub-classify the disease, resulting in potential inadequate therapeutic management of patients and subsequent poor clinical outcomes. Substantial effort is therefore put in cancer research to develop methods and find new biomarkers efficiently identifying and characterizing breast tumor cells. Moreover it is now well-recognized that the intensive cross-talk between cancer cells and their microenvironment (including non-tumor cells) highly influences cancer progression. Recently, a growing body of clinical evidence reported the prognostic and predictive value associated with the presence of tumor infiltrating lymphocytes (TILs) in the microenvironment of breast tumors. Although the evaluation of TILs would be of great value for the management of patients and the development of new immunotherapies, it is currently not assessed in routine practice. Furthermore Fourier transform infrared (FTIR) imaging has shown its usefulness to study a panel of human cancers. Infrared (IR) spectroscopy coupled to microscopy provides images composed of multiple spectra reflecting the biochemical composition and subtle modifications within biological samples. IR imaging therefore provides useful information to improve breast cancer identification and characterization. The ultimate aim of this thesis is to improve breast cancer diagnosis using FTIR imaging to better identify and characterize cancer cells and the tumor microenvironment of breast cancers. In a first step we carried out a feasibility study aiming at evaluating the impact of the sample fixation process on IR spectra. While spectra were undeniably influenced by this biochemical alteration, our results indicated that closely-related cell types were influenced similarly and could still be discriminated on the basis of their spectral features. We then demonstrated the capability of IR imaging to discriminate a tumor from a normal tissue environment based on the spectral features of tumor cells and the surrounding extracellular matrix. A particular focus was placed on the identification of lymphocyte spectral signatures of cells isolated from blood or present within secondary lymphoid organs such as tonsils. Our results revealed that IR imaging was sensitive enough to discriminate lymphocyte subpopulations and to identify a particular spectral signature that we assigned to lymphocyte activation. Finally we highlighted the potential value of IR imaging as complementary tool to identify and characterize TILs in breast tumor samples. Altogether, our results suggest that IR imaging provides interesting and reliable information to improve breast cancer characterization and to assess the immune microenvironment of breast tumors./
Le cancer du sein est le carcinome le plus fréquent chez la femme. C’est une maladie très hétérogène du point de vue histologique, de la réponse thérapeutique et de l’évolution clinique. Une détection rapide et précise de la maladie est cruciale, un diagnostic du cancer du sein dès les premiers stades de la maladie permet une meilleure prise en charge du patient et est directement associé à un meilleur pronostic. Néanmoins la classification actuelle des cancers du sein ne permet souvent pas de caractériser la maladie de manière précise, ce qui donne lieu à la mise en place de traitements moins ciblés et une évolution clinique peu favorable. Pour remédier à cela, des efforts conséquents sont réalisés en recherche, dans le but de mettre au point des méthodes capables d’identifier et de caractériser les cellules tumorales. De plus il est actuellement reconnu que le micro-environnement tumoral (composé des cellules non-tumorales) influence fortement la progression du cancer. Récemment de nombreuses études ont montré que la présence de lymphocytes au niveau des tumeurs mammaires (TILs) était corrélée à un meilleur facteur pronostic et prédictif. Bien que l’évaluation des TILs soit de grande importance dans le cadre des immunothérapies, cet élément n’est actuellement pas pris en compte dans les analyses de routine. Par ailleurs, l’imagerie infrarouge par transformée de Fourier (FTIR) a démontré son utilité dans l’étude de plusieurs cancers humains. La spectroscopie infrarouge (IR) couplée à la microscopie fourni des images composées de multiples spectres qui reflètent la composition biochimique et les modifications dans les échantillons biologiques. De ce fait l’imagerie infrarouge procure des informations utiles pour améliorer l’identification et la caractérisation du cancer du sein. L’objectif général de cette thèse est d’améliorer le diagnostic du cancer du sein par imagerie FTIR pour mieux identifier et caractériser les cellules cancéreuses et le micro-environnement tumoral des tumeurs mammaires. Dans un premier temps nous avons effectué une étude de faisabilité afin d’évaluer l’impact du protocole de fixation des tissus sur les spectres IR. Bien que les spectres soient indéniablement influencés par cette altération biochimique, nos résultats indiquent que des types cellulaires proches sont influencés de manière similaire et peuvent donc être discriminés sur base de leurs caractéristiques spectrales. Nous avons ensuite démontré la capacité de l’imagerie IR de distinguer un environnement tumoral d’un environnement normal sur base des particularités spectrales des cellules tumorales et de la matrice extracellulaire. Une attention particulière a ensuite été portée afin d’identifier des signatures spectrales de cellules immunitaires du sang et au sein d’organes lymphoïdes secondaires, tels que les amygdales. Nos résultats ont révélé que l’imagerie IR permet d'identifier une signature spectrale particulière, que nous avons associée à une stimulation lymphocytaire. Finalement nous avons mis en évidence l’utilité de l’imagerie IR en tant qu’outil complémentaire pour identifier et caractériser les TILs dans les échantillons tumoraux mammaires. De manière générale, nos résultats suggèrent que l’imagerie IR fournit des informations intéressantes et fiables pour améliorer la caractérisation et l’évaluation du micro-environnement immunitaire dans les tumeurs mammaires.
Doctorat en Sciences agronomiques et ingénierie biologique
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Sapir, Ashi [Verfasser], Harald [Akademischer Betreuer] Kolmar, and Felix [Akademischer Betreuer] Hausch. "Evaluation of Yeast Display Fab Libraries Derived from Tumor Infiltrating B Cells / Ashi Sapir ; Harald Kolmar, Felix Hausch." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2020. http://d-nb.info/1203801823/34.
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Philippi, Melanie Verfasser], Stefan [Akademischer Betreuer] [Dübel, and Andreas [Akademischer Betreuer] Gerstner. "Discovery of novel therapeutic antibodies and targets using tumor-infiltrating B cells / Melanie Philippi ; Stefan Dübel, Andreas Gerstner." Braunschweig : Technische Universität Braunschweig, 2020. http://d-nb.info/1210642255/34.
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Hao, Jingcheng [Verfasser], and Jens [Akademischer Betreuer] Werner. "Influence of perivascular tumor infiltrating leukocytes on survival after resection of early hepatocellular carcinoma / Jingcheng Hao ; Betreuer: Jens Werner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1184202516/34.
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Schmidt, Leah Marie. "Investigating functions of tumor-infiltrating natural killer cells in genetically-engineered mouse models of non-small cell lung cancer." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104480.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
The immune system has long been hypothesized to play a role in restraining tumor growth, but compelling evidence for this role evaded scientists for the better part of a century. After many years of skepticism, the field of cancer immunology has recently undergone a major revolution. The success of modern immunotherapeutics has transformed the arenas of oncology and drug development. Large efforts are now focused on understanding the factors that dictate patient responses to immunotherapy, for the identification of possible points of intervention to expand the fraction of patients who benefit from therapy. The majority of approved immunotherapeutics directly target adaptive immune effectors. However, emerging evidence suggests that these treatments preferentially benefit patients with pre-existing immune responses against tumors, and patients who fail therapies often harbor tumors that are poorly infiltrated by adaptive immune cells. I have explored the role of an innate immune effector known for its capacity to kill tumor cells and its importance in stimulating and shaping adaptive immune responses, the natural killer (NK) cell. To this end, I developed a new system for assaying NK cell function in the context of established, autochthonous lung cancer, by engineering vectors for producing tumors with inducible NK cell activating ligands. Using this model, I have shown that NK cells in established tumors exhibit dysfunctional phenotypes, but their responses can be boosted by providing activating stimuli. Strikingly, stimulation of NK cells results in the recruitment of adaptive immune cells to tumors. By developing a next-generation model for inducing activating NK cell ligands in tumors engineered to express T cell antigens, I demonstrated that NK cell activation in immunogenic tumors results in effective immune responses that restrain tumor growth, highlighting the potential for cooperation between innate and adaptive arms of the immune system in anti-tumor immunity. Finally, I developed a novel immunotherapeutic molecule for stimulating NK cell responses against cancer cells. Bifunctional molecules are an emerging class of anti-cancer agents, designed to target immune effectors against tumors. I produced and performed initial functional testing on a bifunctional molecule that stimulates NK cell responses against tumors by 'decorating' the surface of cancer cells with activating NK cell ligands. I demonstrated that this bifunctional molecule induces NK cell cytotoxicity against tumor targets. Based on this work, we hypothesize that strategies for stimulating NK cells in tumors may enhance the efficacy of T cell-targeted therapies in the treatment of cancer.
by Leah Marie Schmidt.
Ph. D.
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Hamanishi, Junzo. "Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer." Kyoto University, 2009. http://hdl.handle.net/2433/124273.
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Andzinski, Lisa Christin [Verfasser], and Dirk [Akademischer Betreuer] Heinz. "Influence of IFN-beta on the life span and apoptosis of tumor infiltrating neutrophil granulocytes / Lisa Christin Andzinski ; Betreuer: Dirk Heinz." Braunschweig : Technische Universität Braunschweig, 2014. http://d-nb.info/1175820474/34.
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De, Silva Jasenthu L. P. "The role of the transcription factor FOXP1 in the immune response to breast cancer." Doctoral thesis, Universite Libre de Bruxelles, 2018. https://dipot.ulb.ac.be/dspace/bitstream/2013/264152/4/Thesis.pdf.
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Breast cancer (BC) was not initially considered an immunogenic tumor; however, recent data show that immune-related factors are associated with patient prognosis and the response to treatment. Several large adjuvant clinical trials have shown that tumor infiltrating lymphocytes (TIL) are significantly associated with a better prognosis and can also predict responsiveness to pre-operative chemotherapy, particularly in the triple negative (TN) & HER2+ BC subtypes (Carsten Denkert et al. 2010; Loi et al. 2013a). Recently, the presence of ectopic lymph node-like structures characterized by distinct T and B cell zones, called tertiary lymphoid structures (TLS), were identified adjacent to the tumor (Gu-Trantien et al. 2013) in 60% of BC (Buisseret et al. 2017b) and linked with a good prognosis (Gu-Trantien et al. 2013). The mechanisms involved in TLS formation and activities and their impact on tumor immunity is relatively unknown. TIL infiltration and TLS formation are likely regulated, in part, by transcription factors (TF) that control cytokine/chemokine production within the tumor microenvironment (TME) (Pimenta and Barnes, 2014). One such TF, the forkhead box protein 1 (FOXP1) is abnormally expressed in various human tumors and has a known role in regulating immune cell functions. Contradictory data on FOXP1 expression together with a lack of information on its immune regulation led us to explore its role in this tumor type. The first part of this thesis research focused on FOXP1-mediated regulation in BC. Gene/protein analysis was examined in the four BC molecular subtypes, revealing its enriched expression in estrogen receptor positive (ER+) tumors (Luminal A/B). Luminal BC is generally less infiltrated compared with frequently high TIL infiltration in ER negative (ER-) tumors (i.e. HER2+ and TN) [reviewed in (Solinas et al. 2017a) and (Loi et al. 2014)]. We found that high FOXP1 expression in a cohort of untreated primary BC was significantly associated with a lower TIL and fewer TLS compared to FOXP1 low (FOXP1lo) tumors. This observation led us to investigate the effect of FOXP1 on cytokines and chemokines potentially involved in TIL recruitment and/or TLS formation. BC cancer cell lines were used to silence [MCF7; FOXP1hi] or overexpress [MDA-MB-231; FOXP1lo] FOXP1 expression. FOXP1 repression upregulated a number of cytokines and chemokines involved in T and B cell migration and function, while FOXP1 overexpression repressed a majority of the same factors. Expression analysis of the major T and B cell cytokine and chemokine genes was performed for FOXP1lo and FOXP1hi primary BC. These data reveal that FOXP1hi BCs have significant decreases in CXCL9, CXCL10, CXCL11, CXCL13, CX3CL1, CCL20, IL2, IL21, granzyme B and IFNγ and high levels of the immunosuppressive cytokines, IL10 and TGFβ. We next performed a lymphocyte migration assay using primary tumor supernatants prepared from FOXP1lo and FOXP1hi BC finding significantly decreased migration of total CD45+ lymphocytes, B cells, helper (CD4+) and cytotoxic (CD8+) T cells using FOXP1hi compared to FOXP1lo SN. Overall, our data suggest that FOXP1 plays an important role in repressing anti-tumor immune responses by negatively regulating TIL migration directed by specific cytokines and chemokines.The second part of this thesis research focused on the role FOXP1 plays in BC TLS. FOXP1 expression in T and B cell TIL and TLS was evaluated using RT-qPCR, multicolor flow cytometry, immunofluorescence (IF) and immunohistochemistry (IHC) and fresh, fixed and frozen breast tissues. Based on the FOXP1 expression two types of TLS were identified in BC: 1) TLS containing a germinal center (GC-TLS) and 2) TLS lacking a GC (non-GC-TLS). Examination of proteins specifically associated with active humoral immune responses allowed us to identify GC-TLS but not non-GC-TLS as functional. Gene expression analysis of micro-dissected tissues revealed distinct immune profiles that characterize B cell follicles in tonsils and spleen as well as aggregates, non-GC-TLS and GC-TLS in BC. This analysis further demonstrates that ongoing cell-mediated immune responses are associated with GC-TLS. The findings from this thesis research add important information to our understanding of how immune responses are initiated and maintained in BC and provide further insight into the identification and organization of functional immune responses at the tumor site.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
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Röhle, Kevin [Verfasser], and Stefan [Akademischer Betreuer] Stevanovic. "Characterization of tumor-infiltrating lymphocytes in ovarian cancer and development of a peptide-based anti-cancer vaccine / Kevin Röhle ; Betreuer: Stefan Stevanovic." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1199393770/34.
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Ivana, Kolarov Bjelobrk. "Klinička vrednost određivanja prisustva tumor infiltrišućih limfocita u bolesnica sa karcinomom dojke." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2016. http://www.cris.uns.ac.rs/record.jsf?recordId=96484&source=NDLTD&language=en.
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UVOD: Glavni problem u lečenju karcinoma dojke je kako na osnovu kliničke klasifikacije i morfoloških osobina tumora predvideti njegovo dalje ponašanje. Vrlo često ni kombinacija standardnih prognostičkih faktora ne daje odgovor o potrebi davanja adjuvantne hemioterapije. U cilju sprovođenja adekvatne dalje terapije karcinoma dojke i otkrivanja agresivnih tipova tumora, a nakon hirurškog lečenja, postoji stalna potreba za pronalaženjem novih pokazatelja pomoću kojih bi se identifikovale bolesnice koje imaju povećan rizik od razvoja relapsa bolesti. CILJEVI: Ciljevi su bili da se utvrdi prisustvo, lokalizacija i distribucija tumor infiltrišućih limfocita, kako ukupnih, tako i CD4+ i CD8+ T limfocita u tumoru dojke, njihova povezanost sa standardnim prognostičkim parametrima, kao i njihov prognostički značaj tj. razlike u nivou infiltracije limfocita u tumoru u odnosu na pojavu relapsa bolesti i dužinu preživljavanja. METOD: Istraživanjem je obuhvaćeno 120 bolesnica sa invazivnim duktalnim karcinomom, sa tumorom lokalizovanim samo u dojci, bez zahvatanja kože i grudnog mišića, sa veličinom tumora do 5 cm, bez udaljenih visceralnih i koštanih metastaza, koje su operisane u Institutu za onkologiju Vojvodine. U istraživanje su uključene bolesnice bez metastaza u limfnim čvorovima pazušne jame i bolesnice sa metastazama u limfnim čvorovima pazušne jame. Istraživanjem nisu obuhvaćene bolesnice koje su primale neoadjuvantnu (preoperativnu) hemioterapiju, kao ni bolesnice sa multifokalnim i multicentričnim tumorima. REZULTATI: Gust limfocitni infiltrat uočen je u 14% tumora dojke, umeren limfocitni infiltrat uočen je u 38%, a oskudan u 43% tumora dojke. Limfocitni infiltrat nije uočen u 5% tumora. Gust infiltrat CD4+ limfocita uočen je u 8% tumora dojke, umeren u 44%, a oskudan u 43% tumora dojke. CD4+ limfociti nisu uočeni u 5% tumora. Gust infiltrat CD8+ limfocita uočen je u 1% tumora dojke, umeren u 23%, a oskudan u 66% tumora dojke. CD8+ limfociti nisu uočeni u 10% tumora. Utvrđena je pozitivna povezanost između nivoa TIL-a i CD4+ limfocita i veličine tumora, histološkog stepena diferentovanosti tumora, prisustva metastaza u limfnim čvorovima pazušne jame, HER-2 statusa, tripl negativnog tumora i relapsa bolesti. Utvrđena je negativna povezanost između nivoa TIL-a i CD4+ limfocita i estrogen i progesteron receptora, kao i godina starosti. Utvrđena je pozitivna povezanost između nivoa CD8+ limfocita i histološkog gradusa tumora, kao i HER-2 statusa. Utvrđena je negativna povezanost između nivoa CD8+ limfocita i estrogen i progesteron receptora, kao i godina starosti. ZAKLJUČAK:Rezultati ovog istraživanja pokazuju povezanost tumor infiltrišućih limfocita i CD4+ limfocita sa brojnim negativnim prognostičkim faktorima, te kraćim vremenom slobodnog intervala bez bolesti, što sve ukazuje na to da su tumor infiltrišući limfociti kao i CD4+ limfociti loš prognostički faktor kod bolesnica sa rakom dojke.INTRODUCTION: The main problem in the treatment of breast cancer that based on clinical classification and morphological characteristics of the tumor to predict its future behavior. Very often, not a combination of standard prognostic factors does not answer the need of giving adjuvant chemotherapy. In order to implement adequate further treatment of breast cancer and detection aggressive types of tumor, after surgical treatment, there is a constant need to find new indicators by which we can identify patients who have an increased risk of relapse. OBJECTIVES: The objectives were to determine the presence, localization and distribution of tumor infiltrating lymphocytes, in total, as well as CD4+ and CD8+ T lymphocytes in breast cancer, their correlation with standard prognostic parameters, as well as their prognostic value i.e. differences in the level of infiltration of lymphocytes in a tumor in relation to the occurrence of disease relapse and survival. METHOD: The study included 120 patients with invasive ductal carcinoma, tumor localized only in the breast without involvement of the skin and pectoral muscle, the size of tumors up to 5 cm without distant visceral and bone metastases, which are operated at the Institute of Oncology. The study included patients without metastases in axillary lymph nodes and patients with metastases in axillary lymph nodes. The research not covered by patients receiving neoadjuvant chemotherapy, or patients with multifocal and multicentric tumors. RESULTS: The high amount of lymphocytic infiltrate was observed in the 14% a breast tumor, a moderate amount of lymphocytic infiltrate was observed in 38%, and the low in 43% breast tumors. Lymphocytic infiltrate was not observed in 5% of the tumor. High CD4+ lymphocyte infiltration was observed in 8% of breast, moderate in 44%, and the low in 43% of breast tumors. CD4+ lymphocytes were not observed in 5% tumors. High infiltration of CD8+ lymphocytes was observed in 1% of breast, moderate in 23%, and the low 66% breast tumors. CD8+ lymphocytes have not been observed in 10% tumors. There is a positive correlation between the level of TIL and CD4+ lymphocytes and tumor size, histological grade of tumor differentiation, presence of metastases in axillary lymph nodes, HER-2 status, triple negative tumors and relapses of disease. There was a negative correlation between the level of TIL and CD4+ cell counts and estrogen and progesterone receptors, as well as age. There is a positive correlation between the level of CD8+ cells and histological grade of the tumor, and HER-2 status. There was a negative correlation between the level of CD8+ lymphocytes and estrogen and progesterone receptors, as well as age. CONCLUSION: The results of this study demonstrate the association between tumor infiltrating lymphocytes and CD4+ lymphocytes with a number of negative prognostic factors, and shorter free interval without the disease, all of which indicates that the tumor infiltrating lymphocytes and CD4+ lymphocytes bad prognostic factor in patients with breast cancer.
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Honkanen, T. (Tiia). "More efficient use of HER targeting agents in cancer therapy." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526223445.
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Abstract Cancer treatments have remarkably improved over the past years since targeted therapies and immunotherapy have been introduced to the field of oncology. The benefit of these new therapies is often limited, however, by de novo or acquired therapy resistances, which should be noticed when making clinical decisions. In this current work, we studied the prognostic and predictive values of several immunological markers in metastatic HER2-positive breast cancer treated with trastuzumab, because trastuzumab is still given to patients according to the HER2 status only, without certainty of tumor response. We also determined the role of HER2 and HER3 for cancer stem cells (CSC) in ALK translocated non-small cell lung cancer (NSCLC) cell lines since the CSCs are causing therapy resistance and cancer recurrence. The results demonstrated that a high number of cytotoxic T cells, together with a high number of M1-like macrophages in the center of the tumor (CT), are promising and independent prognostic factors in HER2-positive breast cancer. These markers together also can predict the progression of the disease and the length of trastuzumab discontinuation in tumor response. Expression of HER2 and HER3 increased the stem-like properties of ALK translocated NSCLC cells, which were decreased when the expressions were downregulated. HER2-HER3-dependent CSCs also mediated the ALK therapy resistance. In conclusion, this study suggests that patients with a favorable immunological tumor profile (high number of cytotoxic T cells and M1-like macrophages in the CT) could be treated in a less-intensive manner, that trastuzumab discontinuation could be feasible for these patients, and that targeting of HER2 and HER3 receptors can lead to more effective killing of cancer stem-like cells and should be further studiedTiivistelmä Syöpähoidot ovat kehittyneet huomattavasti, kun kohdennetut hoidot ja immunologiset hoidot ovat tulleet perinteisten hoitojen rinnalle. Usein näiden hoitojen hyötyä kuitenkin rajoittaa jo olemassa oleva lääkeresistenssi tai sen kehittyminen, mikä tulisi ottaa huomioon hoitoja suunniteltaessa. Tässä työssä tutkittiin immunologisia merkkiaineita, joilla voitaisiin ennustaa trastutsumabi-hoidon vastetta sekä potilaiden ennustetta levinneessä HER2-positiivisessa rintasyövässä. Tällä hetkellä trastutsumabi-hoitopäätös tehdään pelkän HER2-geenimonistuman mukaan ilman varmuutta siitä, hyötyykö potilas oikeasti hoidosta. Lisäksi tutkimme HER2- ja HER3-reseptorien merkitystä syövän kantasoluille ALK-translokoituneessa ei-pienisoluisessa keuhkosyövässä (NSCLC), sillä syövän kantasolut ovat yksi merkittävimmistä tekijöistä lääkeresistenssin kehittymisessä ja syövän uusiutumisessa. Työssä havaittiin, että kasvaimen keskellä oleva suuri määrä sytotoksisia T-soluja sekä M1-tyypin makrofageja on yhteydessä potilaiden parempaan ennusteeseen ja että kyseiset merkkiaineet ovat toisistaan riippumattomia. Merkkiaineet pystyivät ennustamaan myös taudin etenemistä sekä trastutsumabi-hoitokeskeytyksen pituutta. HER2- ja HER3-proteiinien tuotto lisäsi ALK-translokoituneiden NSCLC-solujen kantasolumaisia ominaisuuksia, jotka puolestaan vähenivät, kun proteiinien tuotto estettiin. Lisäksi HER2-HER3 -riippuvaiset syövän kantasolut säätelivät lääkeresistenssiä kyseisessä taudissa. Työn tulokset viittaavat siihen, että potilaita, joilla on suotuisa kasvaimen immunoprofiili (suuri määrä sytotoksisia T-soluja ja M1-tyypin makrofageja kasvaimen keskellä) pystyttäisiin hoitamaan keveimmillä hoidoilla ja HER2-hoitokeskeytys voisi olla mahdollinen näillä potilailla. Lisäksi työ korostaa HER2- ja HER3-reseptorien kohdentamista syövän kantasolumaisten solujen tehokkaamman tuhoamisen saavuttamiseksi
Huomautus/Notice Painetussa virheelliset ISBN -tunnukset: ISBN (print) 978-952-42-2343-8 pitäisi olla 978-952-62-2343-8. ISBN (PDF) 978-952-42-2344-5 pitäisi olla 978-952-62-2344-5. Printed version has incorrect ISBNs: ISBN (print) 978-952-42-2343-8 it should be 978-952-62-2343-8. ISBN (PDF) 978-952-42-2344-5 it should be 978-952-62-2344-5
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Chen, HwuDauRw 1958. "Growth of immunogenic skin tumors: Infiltrating leukocytes." Thesis, The University of Arizona, 1989. http://hdl.handle.net/10150/291654.
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Subpopulations of tumor infiltrating leukocytes in immunogenic skin tumors were identified with monoclonal antibodies. The tumors studied included primary UV-induced tumors and JB/MS melanomas, which survive in the host by immunosuppression of the immune response. The proportions of nucleated cells in primary UV-induced tumor cell suspensions which reacted with monoclonal antibodies were: 52% Mac-1+, 21% Lyt-1+, 13% Lyt-2+, 7% L3T4+, and 8% IL-2R+. Thus there was a high proportion of cells of the macrophage lineage in the growing UV-induced tumors. In JB/MS melanoma cell suspensions the mean proportion of macrophages was 6.4%, and total T lymphocytes (Lyt-1) averaged only 5.5%. Thus, there was little leukocytes infiltration into JB/MS melanoma, suggesting that chemotaxis was defective. The high level of macrophages and T cells in the primary UV-induced tumors indicates that chemotaxis was intact. Therefore, either the tumorcidal capacities of the macrophages and Tc were insensitive to activated macrophages and to Tc cells.
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Bonneau, Claire. "Étude des mécanismes de récidive métastatique dans les cancers du sein luminaux de stade précoce : impact du microenvironnement tumoral Caractérisation moléculaire des cancers du sein en pratique clinique A subset of activated cancer associated fibroblasts is associated with distant relapse in early luminal breast cancers." Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2365&f=17162.
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Les cancers du sein de stade précoce constituent un enjeu de santé publique du fait de leur fréquence élevée (70% des nouveaux cas diagnostiqués). Parmi eux, les cancers luminaux (exprimant les récepteurs hormonaux sans surexpression de l’HER2) de stade T1N0, de moins de 2cm sans envahissement ganglionnaire, ont un pronostic spontanément favorable et font ainsi l’objet de peu d’études dédiées. Néanmoins certaines de ces patientes (5 à 10% à 10 ans) vont récidiver avec des métastases à distance et mourir. L’identification de facteurs pronostiques pour ces tumeurs et une meilleure compréhension des mécanismes de récidive pourraient permettre de discriminer les tumeurs réellement indolentes pour lesquelles le traitement pourrait être diminué et au contraire, les tumeurs les plus à risque de récidive pour lesquelles un traitement devrait être renforcé. L’objectif de ce travail de thèse était d’identifier les mécanismes de la récidive métastatique dans les cancers du sein luminaux de stade T1b-cN0M0 au diagnostic en analysant plus spécifiquement le microenvironnement tumoral. Pour cela, nous avons constitué une cohorte de patientes ayant eu un cancer du sein T1b-cN0, de type luminal (exprimant les récepteurs hormonaux sans surexpression de l’HER2) de type cas (patientes avec récidive métastatique à distance) / témoin (patiente sans récidive à distance), à partir de la cohorte de patientes suivies à l’Institut Curie. Les témoins étaient choisis appariés aux cas sur les principaux facteurs pronostiques connus : âge, grade tumoral et prolifération tumorale estimée par le Ki67. Nous avons ensuite évalué les facteurs de récidive dépendant des cellules tumorales. En analyse univariée, on montre qu’une moins bonne différenciation (baisse de l’expression de la E-cadhérine) est associée à la récidive. Par ailleurs, le score de récidive prédit par la signature transcriptomique ProsignaTM est plus élevé chez les cas que chez les contrôles sans que la discrimination entre les deux ne soit parfaite pour cette population de cancers du sein. L’originalité de notre étude reposait sur l’étude détaillée du microenvironnement tumoral. Sur le plan immunologique, l’analyse systématique quantitative et qualitative, en immunohistochimie, de l’infiltrat immun montre une absence d'association avec les lymphocytes B, macrophages et cellules dendritiques. En revanche, on observe une baisse des lymphocytes T CD4+ tumoraux chez les cas, sans autres association concernant les différents sous-types de lymphocytes T. Dans la continuité des travaux déjà réalisé au laboratoire du Dr Fatima Mechta-Grigoriou, l’analyse des différents sous-types de fibroblastes associés au cancer (CAF) dans notre cohorte révélait que les cas étaient plus spécifiquement enrichis en CAF activés de type CAF-S1 alors que la quantité globale de stroma ne soit pas associée à la récidive. Ici, l’action des CAF-S1 est médiée par la cadhérine-11 qui augmente les capacités de migration et invasion des cellules tumorales in vitro par stratégie siRNA. En analyse multivariée, les caractéristiques du microenvironnement et en particulier l’enrichissement en CAF-S1 restent significativement associées à la récidive.En conclusion, nous avons identifié que la survenue de métastases dans les cancers du sein luminaux de stade précoce repose sur des mécanismes associés au micro-environnement tumoral tels que la présence de CAF-S1 et leur expression de la cadhérine-11, indépendamment des cellules tumorales elles-mêmes. L’enrichissement en CAF-S1 dans le stroma tumoral était également un facteur de mauvais pronosticPurpose: Early luminal breast cancers (BC) represent 70% of newly diagnosed BC. Their prognosis is generally favorable but some patients (around 5 to 10% at 10 years) will relapse with distant metastases and most of them will die. Because this dismal prognosis concerns a small number of patients, T1N0 BC have been rarely studied. The aim of this work was to identify the mechanisms of metastatic recurrence in luminal breast cancers T1b-cN0M0 at diagnosis by deciphering characteristics of both epithelial cancer cells and their surrounding tumor microenvironment (TME). Experimental Design: We constituted a cohort of luminal T1b-cN0 BC patients with metastatic recurrence (defined as "cases”) and corresponding "controls" (i. e. patients without metastatic relapse) matched (1:1) to cases on the main known prognostic factors: age, tumor grade and tumor proliferation (assessed by Ki67). Results: We found that properties in both epithelial compartment and TME are indicative of relapse in early luminal breast cancers. In univariate analysis, the loss of differentiation (assessed by the reduced expression of CDH1/E-cadherin) in cancer cells is associated with recurrence, as also predicted by high ROR score using ProsignaTM test. In TME, quantitative and qualitative immunohistochemical analyzes reveals that “cases” are characterized by a significant decrease in CD4+ T lymphocytes and an accumulation of a particular subset of Cancer Associated Fibroblasts (CAF-S1) compared to “controls”, without any other association of T lymphocyte subtypes, B lymphocytes, macrophages or dendritic cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, which demonstrates their biological and clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic properties are -at least in part- mediated by CDH11/Osteoblast cadherin, consistent with the fact that the bones are a major site of metastases in these patients. Conclusions: Distant recurrence in early luminal BC is strongly associated with TME features, such as the presence of CAF-S1 and their expression of CDH11. This is independent of tumor cells and represents a new prognostic factor of distant relapse in early luminal BC patients. This could justify targeted therapies against CAF-S1 or CDH11 in these cases
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Santos, Bianca Maria Alves dos. "Microrregiões metabólicas no carcinoma ductal infiltrativo de mama humana." Universidade de São Paulo, 1999. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-14112017-122438/.
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No presente estudo analisou-se o metabolismo de glicose e glutamina, através da determinação da atividade enzimática, em carcinomas ductais infiltrativos de pacientes sem tratamento. As pacientes estavam na faixa etária entre 32 e 68 anos e cerca de 75% no período pós-menopausa. Os tumores estudados apresentavam graus de diferenciação e tamanho distintos; no entanto, sem metástases distantes. Os seguintes parâmetros foram analisados: a) efeito da insulina sobre o consumo de glicose em fatias tumorais, b) atividades das enzimas da via glicolítica e da glutaminase nas áreas do centro e periferia do tumor, c) parâmetros cinéticos da piruvato quinase purificada. Os resultados foram comparados entre os tumores e a glândula mamária e entre as áreas centrais e periféricas dos próprios tumores. O consumo de glicose mostrou-se maior nos carcinomas, principalmente no centro que na periferia do tumor, mas não foi alterado pela insulina. Não houve relação entre o consumo de glicose e o tamanho dos tumores, nem com o grau histológico. Inversamente, na glândula mamária, a insulina (100 µU/ml) aumentou a captação de glicose. A concentração de lactato produzida, pela incubação das fatias tumorais com glicose, foi significativamente maior nos carcinomas do que na glândula mamária, equivalente ao aumento do fluxo glicolítico. A atividade das enzimas da via glicolítica foi maior nos carcinomas em comparação ao tecido normal. A atividade foi também significativamente diferente tanto na comparação entre as áreas do centro e periferia do tumor, quanto considerando-se o grau de diferenciação dos carcinomas. Nas áreas centrais, as atividades enzimáticas foram mais elevadas, enquanto que considerando-se os graus histológicos, tumores menos diferenciados apresentaram atividades mais elevadas que os de maior grau de diferenciação. Dentre as enzimas reguladoras da glicólise, a piruvato quinase apresentou a maior atividade em comparação à hexoquinase e fosfofrutoquinase-1. Este aumento foi significativamente maior nos carcinomas associados com comprometimento de linfonodos axilares. A piruvato quinase purificada mostrou Km de 0,23 mM para fosfoenolpiruvato e 0,3 mM para ADP. ATP inibiu em 40% a atividade da enzima, enquanto que alanina, fenilalanina e cálcio inibiram em 55%, 84% e 93% a atividade da enzima, respectivamente. A frutose 1,6bifosfato induziu 36% de ativação e reverteu em 100% a inibição causada por fenilalanina, em 87% aquela da alanina e cerca de 56% para ATP, mas não reverteu a inibição por cálcio quando em concentrações saturantes e apenas em 15% em concentrações sub-saturantes. O padrão eletroforético da piruvato quinase diferiu da mama e tumores benignos (fibroadenomas), o que pode representar um marcador de malignidade. A atividade das enzimas citrato sintetase e glicerol-3-fosfato desidrogenase mostrou-se diminuída de acordo com o aumento da atividade glicolítica e relacionou-se diretamente com o grau de diferenciação dos carcinomas. Tumores diferenciados mostraram maior atividade. A atividade da glutaminase foi maior nos carcinomas em comparação à glândula mamária, sendo ainda maior nas áreas do centro do tumor que nas áreas periféricas. O grau de diferenciação também correlacionou-se com a atividade da enzima, mas não foram observadas diferenças significativas quando considerou-se o tamanho tumoral. As diferenças metabólicas observadas podem associar-se ao comportamento clínico heterogêneo entre pacientes com o mesmo tipo de carcinoma.Glucose and glutamine metabolism of infiltrating ductal carcinomas of untreated patients was studied by determining enzyme activities. The patients were between 32 and 68 years old and about 75% were in post-menopausal period. The tumors have different histological grading and sizes but no distant metastasis. The following parameters were analysed: a) effect of insulin on glucose uptake by tumor slices, b) glycolytic (hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase) and glutaminolytic (glutaminase) enzyme activities, c) kinetic parameters of purified pyruvate kinase. The results were compared to those of mammary gland and between center and periphery regions of the tumors. Glucose, consumption was higher in the carcinomas, compared to mammary gland, specially in the solid region (center) than in the periphery, but it was not altered by insulin. No correlation was found between glucose consumption rate and the tumor size or differentiation grading. Inversely, in the mammary gland, insulin (100 µU/ml) increasead glucose uptake. Lactate production was significantly higher in the carcinomas than in the mammary gland according to the glycolytic flux. The glycolytic enzyme activities were higher in the carcinoma than in the mammary gland. The enzyme activities were more elevated in the center as compared to peripheric areas of the tumor. In the tumor center, the enzyme activities were highest in the undifferentiated carcinoma. Pyruvate kinase (PK) presented higher activity than phosphofructokinase 1 and hexokinase activities. Purified PK from the tumor presented a reduced Km for phosphoenolpyruvate (0,23 mM) and ADP(O,3 mM). ATP inhibited 40% of the enzyme activity, while alanine, phenilalanine and calcium inhibited it by 55%, 84% and 93%, respectively. Fructose 1,6 bisphosphate enhanced 36% of enzyme activity and reverted by 100% the inhibition caused by phenilalanine, 87% that of alanine and 56% that of ATP, but did not revert the inhibition by Ca+2 when at saturating concentration, having a capacity of reverting only 15% of the inhibition caused by near-saturating concentration of Ca+2. The citrate synthase and α-glycerol phosphate dehydrogenase activities were reduced according to increase in the glycolytic activity and had a direct correlation with the histological grading. Differentiated tumors had higher activities. Glutaminase activity was elevated in carcinomas as compared to mammary gland, being even higher in the central regions of the tumors. The enzyme activity was also higher in the moderate differentiated tumors than that in the differentiated tumors, but no significant differences were observed when the tumor size was considered. There was a relationship between the data and the clinicai heterogeneity of the disease.
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Oku, Sergio Mitsuo Masili. "Identificação de subtipos moleculares baseada no perfil imunoistoquímico de carcinomas mamários triplo-negativos em mulheres com idade até 45 anos e sua distribuição nas diferentes regiões geográficas do Brasil." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-23082016-093500/.
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INTRODUÇÃO: Carcinomas mamários triplo-negativos correspondem ao grupo heterogêneo de neoplasias mamárias caracterizadas pela ausência de expressão dos receptores de estrogênio e progesterona e sem amplificação ou superexpressão do HER2. São mais prevalentes em mulheres jovens e em afrodescendentes. Eles se associam frequentemente ao fenótipo basal-símile determinado geneticamente, entretanto, incluem também outros tipos moleculares intrínsecos. Metodologias de análise genética de novas gerações têm permitido sua estratificação em subgrupos distintos, o que justifica a heterogeneidade clínica deste grupo de neoplasias. A identificação desses subgrupos através de marcadores imunoistoquímicos de aplicação prática ainda é pouco explorada, embora seja uma ferramenta promissora na sua estratificação e determinação de alvos terapêuticos. OBJETIVOS: Nosso objetivo é explorar os perfis imunoistoquímicos dos carcinomas mamários triplo-negativos em mulheres com idade até 45 anos e investigar possíveis diferenças entre as cinco regiões geográficas brasileiras. MÉTODOS: Selecionamos 118 amostras de tumores de pacientes com idade até 45 anos, com carcinoma invasivo, blocos de parafina disponíveis e perfil imunoistoquímico triplo-negativo, procedentes das cinco regiões geográficas. Estes casos foram revisados quanto à determinação de tipo e grau histológico e as seguintes características anatomopatológicas: contorno do tumor, presença e fração do componente \"in situ\", embolização vascular peritumoral, tipo e grau da reação estromal, presença de necrose tumoral e formação de túbulos pela neoplasia. Foram selecionadas áreas representativas do tumor para construção de blocos de microarranjos de tecido para estudo imunoistoquímico. Foram pesquisados os seguintes marcadores: citoqueratinas basais 5/6 e 14, citoqueratinas luminais 8 e 18, receptor do fator de crescimento epidérmico (EGFR ou HER1), receptor de androgênio, e-caderina, catenina-beta, claudinas 3, 4 e 7, vimentina, actina de músculo liso, p63, ALDH1 e Ki-67. De acordo com a expressão dos marcadores, os tumores foram classificados nos subgrupos basal-símile (expressão de citoqueratina basal 5/6 e/ou EGFR-positivo), claudina-baixo (claudinas e e-caderina-negativos), mesenquimal (vimentina-positivo), apócrino (receptor de androgênio-positivo), mioepitelial (p63 ou actina de músculo liso positivos), com perfil de células tronco (ALDH1 positivo), ou indefinido (padrões negativo para todos os marcadores). Nestes subtipos, a atividade proliferativa foi analisada através da expressão de Ki-67. As neoplasias provenientes das cinco regiões geográficas foram comparadas quanto às características histológicas e perfis imunoistoquímicos. RESULTADOS: A idade das pacientes variou de 26 anos a 45 anos ( média 38,3 +/-4,9 e mediana de 39 anos ). O tipo histológico mais frequente foi o carcinoma de tipo histológico não especial (107/118 casos; 90,7%). Observamos maior proporção de carcinomas de alto grau nas regiões nordeste, sul e sudeste. Os marcadores imunoistoquímicos não mostraram diferenças nas frequências entre as diferentes regiões geográficas. Observamos baixa atividade proliferativa determinada pela expressão do Ki-67 nos subgrupos com expressão do receptor de androgênio (apócrino) e sem expressão de vimentina (padrão não mesenquimal). Os tumores da região Nordeste, Sul e Sudeste apresentaram maior atividade proliferativa. Tumores ricos em linfócitos intratumorais apresentaram menor expressão de marcadores basais e do perfil basal-símile. CONCLUSÕES: Os subtipos moleculares determinados através da expressão imunoistoquímica não mostraram diferenças nas frequências entre as diferentes regiões geográficas. Os tumores das regiões Nordeste, Sul e Sudeste apresentaram maior atividade proliferativa. Os carcinomas ricos em linfócitos intratumorais apresentaram frequência menor do perfil basalBACKGROUND: Triple-negative breast carcinomas (TNBC) correspond to a heterogeneous group of neoplasia characterized by the lack of expression of estrogen and progesterone receptors, and by the absence of amplification or overexpression of HER2. They are more prevalent among African descendants and younger women. They are often associated with the basal-like genetic phenotype; however, other intrinsic molecular types are included. Genomic analyses of next-generation methods have allowed stratification of TN breast carcinomas into distinct subgroups, explaining the clinical heterogeneity of this group of neoplasias. The identification of these subgroups by immunohistochemical markers is not well explored, although it represents a potential useful tool for the stratification and determination of therapeutic targets. OBJECTIVES: Our aim is to explore the TNBC immunohistochemical profile in patients of 45 year-old or younger, and to investigate possible differences among the five Brazilian geographic regions. METHODS: We\'ve selected 118 samples of tumors from patients up to 45 years-old from five Brazilian geographic regions, with invasive carcinoma, available paraffin blocks, and triple-negative immunohistochemical profile. All the cases were reviewed as for determination of histologic type and grading, and the following pathological features: tumor contour, presence and percentage of in situ component, peritumoral vascular embolization, type and grade of stromal reaction, presence of tumoral necrosis, and tubule formation by neoplasia. Representative tumor areas were selected for tissue microarray construction for immunohistochemical study. The following markers were studied: Basal cytokeratins 5/6 and 14; luminal cytokeratins 8 and 18; Epidermal growth factor receptor (EGFR or HER1); androgen receptor; e-cadherin; catenin-beta; claudins (3,4 and 7); vimentin; smooth-muscle actin; p63, ALDH1, and Ki-67. According to the expression of the markers, the tumors were grouped in the basal-like subgroups (basal cytokeratins 5/6 and/or EGFR positive), claudin-low (claudins and/or e-cadherin negative), mesenchymal (vimentin-positive), apocrine (androgen receptor positive), myoepithelial (p63 and/or smooth muscle actin positive), stem-cell (ALDH1-positive), or undefined (negative for all markers). In these subtypes the proliferative activity through the Ki-67 expression was analyzed. Neoplasias from the five regions were compared as for histological characteristics and immunohistochemical profiles. RESULTS: The age of patients ranged from 26 years to 45 years (mean 38.3 +/- 4.9 and median of 39 years). The most common histological type was no special histological type (NST) of carcinoma (107/118 cases, 90.7%). We observed a higher proportion of high-grade carcinomas in the regions Northeast, South and Southeast. Compared to the Midwestern and Northern regions there was no statistically significant difference (p = 0.03). The immunohistochemical markers showed no differences in the frequencies between the different geographical regions. We observed low proliferative activity determined by Ki-67 expression in the subgroups with androgen receptor expression (apocrine) and no expression of vimentin (no mesenchymal pattern). Tumors of the Northeast, South and Southeast have higher proliferative activity. There was a lower frequency of immunohistochemical markers associated with basal molecular type between tumors rich in lymphocytes. CONCLUSIONS: The molecular subtypes determined by immunohistochemical expression have shown no differences in the frequencies among the different geographical regions. Tumors in the Northeast, South and Southeast had higher proliferative activity. Carcinomas rich in intratumoral lymphocytes had lower frequency of basal profile
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Petitprez, Florent. "Integrated analysis and clinical impact of immune and stromal microenvironments in solid tumors Quantitative analyses of the tumor microenvironment composition and orientation in the era of precision medicine Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies Tumor microenvironment quantification tool draws a comprehensive map of the tumor microenvironment of non-hematologic human cancers The mMCP-counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations using gene expression in murine samples Immune sub-classes in sarcoma predict survival and immunotherapy response Intra-tumoral tertiary lymphoid structures are associated with a low risk of hepatocellular carcinoma early recurrence Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer Immune-based identification of cancer patients at high risk of progression Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma PD-L1 expression and CD8+ T-cell infiltrate are associated with clinical progression in patients with node-positive prostate cancer Intratumoral classical complement pathway activation promotes cancer progression." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB104.
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Les tumeurs sont composées de cellules malignes et d'une grande variété de cellules non-tumorales, en particulier des cellules immunitaires qui forment le micro-environnement tumoral (MET). Il a été démontré que la composition du MET était associée au devenir clinique des patients, en termes de survie et de réponses thérapeutiques. Avec le développement récent des immunothérapies qui ciblent des éléments spécifiques du MET, l'immunité anti-tumorale a soulevé un intérêt majeur. Plusieurs méthodologies ont été mises au point afin d'étudier la composition du MET, avec une précision toujours plus grande. En particulier, des méthodes comme MCP-counter permettent d'exploiter les données transcriptomiques de la tumeur entière afin de quantifier les différentes populations qui composent le MET. Le volet méthodologique de ce travail de thèse a ainsi consisté à proposer une amélioration de MCP-counter, en particulier pour l'analyse de données RNA-Seq. Une adaptation de la méthode pour des données issues de modèles murins (mMCP-counter) est également proposée. MCP-counter permet d'analyser rapidement le MET de larges séries de tumeurs. Un second volet de cette thèse consiste en l'application de cette méthode pour établir une classification immunitaire des sarcomes des tissus mous, un type de cancer rare, hétérogène et agressif. Cette classification immunitaire a permis de mettre en évidence des groupes de tumeurs faiblement ou fortement infiltrés, ainsi qu'un groupe marqué par une forte vascularisation. De manière intéressante, la classification immunitaire permet de prédire la réponse des patients aux immunothérapies. Ce travail a aussi démontré un rôle important des structures lymphoïdes tertiaires (SLT). Les SLT sont des structures de type noeud lymphatique composées de lymphocytes B et T qui se forment dans la tumeur ou à proximité de celle-ci. Au sein des SLT, une réponse immunitaire anti-tumorale peut se former et maturer. L'intérêt porté aux SLT est de plus en plus important pour de nombreux types de cancers. Dans la plupart des types de cancer, une forte infiltration de la tumeur par des lymphocytes T, en particulier CD8+, est associée à une meilleure survie des patients. Cependant, le carcinome rénal à cellules claires et le cancer de la prostate sont des exceptions à cette règle. En effet, dans ces deux cancers urologiques, la présence dans la tumeur de lymphocytes T est associée à une survie plus courte des patients, ainsi qu'à une rechute et une progression plus précoce. Ces exceptions sont détaillées dans une troisième partie de cette thèse, par une description minutieuse du MET, ainsi que par l'analyse de l'implication du système du complément. Dans leur ensemble, les résultats présentés dans cette thèse démontrent qu'en combinant différentes méthodes d'analyse, in silico, in situ et in vivo, il est possible d'obtenir une vision extrêmement complète du MET. La connaissance des types cellulaires présents dans la tumeur ainsi que leur orientation fonctionnelle permet de guider le soin apporté aux patients et d'améliorer leur devenir clinique. La description complète du MET ouvre la voie à une médecine personnalisée pour les patients atteints de cancerTumors are composed not only of malignant cells but also contain a vast variety of non-malignant cells, notably immune cells forming the tumor microenvironment (TME). The composition of the TME was shown to be associated with clinical outcome for cancer patients, in terms of survival and therapeutic responses. With the relatively recent development of immunotherapies targeting specific elements of the TME, tumor immunology has risen a strong interest and holds a strong therapeutic potential. Several methodologies have been developed to study the composition of the TME with an increased precision. Notably, some methods such as MCP-counter enable the use of the tumor bulk transcriptome to quantify cell populations composing the TME. The methodological aspect of this PhD project consisted in setting up an enhanced version of MCP-counter that can be readily applied to RNA-Seq data, as well as propose an adaptation of the method for mouse models. Using MCP-counter, the TME of large series of tumors can be easily analyzed. The application part of this PhD work consisted of applying MCP-counter to establish an immune-based classification of soft-tissue sarcoma, a rare, aggressive and heterogeneous cancer type. The immune classification notably allowed to identify immune low and high groups, and a group characterized by a strong vasculature. Interestingly, the classification was notably found to be predictive of the patients' response to immunotherapies. It also highlighted an important role of tertiary lymphoid structures (TLS). TLS are lymph-node-like structures composed of T and B cells that form within the tumor or in close proximity. They are a site of formation and maturation of antitumoral immune responses. TLS are raising a growing interest in many malignancies. In most cancer types, a strong infiltration by T cells, in particular CD8+ T cells, is associated with a favorable clinical outcome. However, clear-cell renal cell carcinoma and prostate cancer are exceptions to this general rule. Indeed, in these urological cancers, an increased infiltration by T cells is associated with a decreased patient survival and with earlier relapse and disease progression. In a third part of this thesis, these exceptions are investigated with more details by scrutinizing the TME, and questioning the implication of the complement system. Overall, this thesis presents how the combination of several analysis methods, in silico, in situ and in vivo, can help achieve an extremely precise description of the TME. Knowing accurately what cell populations and what their functional orientation can help guide patients care and improve clinical outcome. Complete description of the TME opens the way towards personalized medicine for cancer patients
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Higgins, Catherine Ann. "Tumour associated macrophages, tumour infiltrating lymphocytes, apoptotic and mitotic cells in human colorectal cancer." Thesis, University of Ulster, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268556.
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Choi, Ka-man. "Tumour infiltrating lymphocytes (TILs) a prognostic factor for gastric adenocarcinoma /." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B32046431.
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Choi, Ka-man, and 蔡嘉敏. "Tumour infiltrating lymphocytes (TILs): a prognostic factor for gastric adenocarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B32046431.
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Balança, Camille-Charlotte. "Contribution des réponses immunitaires adaptatives spécifiques des antigènes tumoraux à l'efficacité clinique de l'immunothérapie par inhibition de l'axe PD-1/PD-L1." Thesis, Toulouse 3, 2021. http://www.theses.fr/2021TOU30007.
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Les lymphocytes infiltrant la tumeur (TIL) épuisés, sont caractérisés par l'expression de points de contrôle de l'immunité (PCI), par exemple PD-1. Une des approches majeures en immunothérapie, basée sur l'inhibition des PCI, s'est avérée efficace dans le contrôle de la progression tumorale dans plusieurs cancers. Malgré cette avancée, seule une proportion des patients en retire un bénéfice clinique. Afin d'améliorer les réponses à l'inhibition des PCI, il est nécessaire de comprendre les mécanismes impliqués dans l'épuisement des TIL et d'élucider quels lymphocytes T (LT) sont capables de répondre à cette immunothérapie. Au site tumoral, nous mettons en évidence que seuls les LT CD8 spécifiques des antigènes (Ag) tumoraux expriment quatre PCI ainsi que d'autres marqueurs d'épuisement et perdent la molécule de co-stimulation CD28, contrairement au LT CD8 spécifiques circulants. Les TIL CD8 spécifiques sont dysfonctionnels, néanmoins, ils possèdent un potentiel cytotoxique élevé et expriment des marqueurs de résidence. Nous montrons que l'inhibition de PD-1 a une double action sur les LT CD8 spécifiques. Elle rétablit leurs fonctions dans la tumeur et augmente leur prolifération dans la périphérie. De manière importante, l'infiltration des tumeurs par ces TIL spécifiques et épuisés est prédictive de la réponse à la thérapie et de la survie des patients traités par immunothérapie ciblant l'axe PD-1/PD-L1. Les LT CD4 auxiliaires sont essentiels pour l'amorçage de la réponse T CD8. En revanche, leur rôle effecteur dans la tumeur a été moins étudié. Ici, nous montrons que les LT CD4 spécifiques des Ag tumoraux, également épuisés au site tumoral, peuvent être identifiés par des marqueurs qui leur sont propres. Des similarités dans le programme d'épuisement des LT CD4 et CD8 ont été retrouvées. Le blocage de PD-1 sur les TIL CD4 rétablit leur activation, ce qui va permettre la maturation des cellules dendritiques et, par conséquent, l'augmentation de la prolifération des TIL CD8 spécifiques de la tumeur. Nos résultats révèlent que les TIL CD4 et CD8 spécifiques des Ag tumoraux épuisés peuvent être identifiés chez les patients par des marqueurs caractéristiques et qu'ils répondent à l'inhibition du PD-1 en rétablissant les fonctions des LT CD8 de manière directe et indirecte. Ces données identifient des biomarqueurs prédictifs de la réponse à l'immunothérapie et positionnent les LT spécifiques des Ag tumoraux comme des acteurs de la réponse clinique à l'immunothérapie bloquant le PD-1Exhausted tumor-infiltrating lymphocytes (TILs) are characterized by immune checkpoint (IC) expression, for instance PD-1. One of the major immunotherapy approaches, based on IC inhibition, has proved efficient in the control of tumor progression in many cancers. Despite this progress, only a proportion of patients experience clinical benefit. To improve responses to IC inhibitors, understanding mechanisms involved in TIL exhaustion and investigating which T cells are able to respond to immunotherapy are required. We investigated both CD8 and CD4 T-cell exhaustion and its relation to tumor antigen (Ag) specificity and to responsiveness to IC inhibition in cancer patients. We demonstrated that CD8 T-cell exhaustion at the tumor site was only attained by tumor Ag-specific cells that were characterized by the sequential acquisition of ICs and by CD28 loss. Their circulating counterparts expressed less ICs and at lower levels and were CD28+. Specific CD8 TILs were dysfunctional, nonetheless, they maintained high cytotoxic potential and expressed tissue residency markers. We showed that PD-1 inhibition has a dual effect on specific CD8 T cells. It rescued their effector functions at the tumor site and enhanced their proliferation in the periphery. Importantly, the quantity of exhausted and specific TILs was predictive of response to therapy and of survival in patients treated with PD-1-targeting immunotherapy. Assessment of CD4 TIL exhaustion underscored similarities with the CD8 exhaustion program, in particular their specificity for tumor Ag and sequential acquisition of ICs although ICs characterizing terminally exhausted CD4 TILs were different than those found in CD8 TILs. Importantly, PD-1 blockade on CD4 TILs restored their helper functions, leading to dendritic cell maturation and, consequently, increased tumor-specific CD8 T-cell proliferation. Our data imply that under anti-PD-1/PD-L1, effector functions of terminally exhausted CD8 TILs is rescued and the tumor site is replenished by memory CD8 T cells which proliferate following direct blockade of PD-1 and through reinvigoration of the helper activity of tumor Ag-specific CD4 T cells. Our results position tumor Ag-specific T cells as major players of responsiveness to PD-1-blocking immunotherapy and identify predictive biomarkers of response to immunotherapy
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Burgents, Meredith Lynn Flood Patrick M. "CD8 T cell tumor infiltration following Tc1 or Tc2 therapy." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1358.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Oral Biology." Discipline: Oral Biology; Department/School: Dentistry.
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Granier, Clémence. "Expression de récepteurs inhibiteurs sur les lymphocytes T infiltrant les tumeurs du rein : signification biologique et clinique Multiplexed immunofluorescence analysis and quantification of intratumoral PD-1+ Tim-3+ CD8+ T cells Tim-3 expression on tumor-infiltrating PD-1+CD8+ T cells correlates with poor clinical outcome in renal cell carcinoma." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB183.
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L'expression de récepteurs inhibiteurs tels PD-1, TIM-3, LAG-3, TIGIT sur les lymphocytes T participe à l'immunosuppression dans l'environnement tumoral. Le ciblage de PD-1 par les immunothérapies anti-PD-1/PD-L1 notamment révolutionne depuis peu la prise en charge de nombreux types de cancers en particulier dans le mélanome, cancer du poumon et aussi du rein. Dans la plupart des cancers comme dans celui du poumon et le mélanome, l'infiltrat CD8 et la réponse Th-1/IFN-gamma sont associés à un meilleur pronostic, contrairement aux tumeurs du rein et aux hémopathies. Les travaux de ma thèse s'intéressent à la caractérisation de l'expression des récepteurs inhibiteurs des lymphocytes, notamment PD-1 et TIM-3 dans le carcinome rénal et dans le lymphome. Mes travaux de thèse ont été réalisés avec des outils d'exploration du microenvironnement tumoral permettant une analyse multiplexe de nombreux paramètres in situ. En théorie jusqu'à 7 protéines peuvent être mises en évidence à la fois, j'ai pu mettre au point des comarquages de 4 protéines membranaires et/ ou nucléaires + Dapi ainsi que la détection d'ARN in situ dans les tumeurs. L'utilisation d'un outil technologique de microscopie à fluorescence multispectrale a permis une étude fine de la coexpression de PD-1 et Tim-3 sur les lymphocytes T CD8 (LT-CD8) grâce à la visualisation aisée de la colocalisation de ces 3 marqueurs. De la même façon, j'ai mis en évidence de l'expression de leurs ligands PD-L1 et Galectin-9 (Gal-9) dans l'environnement des tumeurs du rein. J'ai démontré que la co-expression de Tim-3 et PD-1 sur les CD8 dans le carcinome rénal avait un rôle délétère aussi bien sur le plan (i) fonctionnel puisque les LT-CD8 sécrétaient moins d'IFN-gamma, (ii) et clinique puisque les patients présentant un infiltrat de LT-CD8 double positifs pour PD-1 et TIM-3 récidivaient plus fréquemment. La présence des ligands PD-L1 et Gal-9 a été mise en évidence dans l'environnement tumoral laissant suggérer des interactions possibles avec les récepteurs inhibiteurs exprimés par les LT. J'ai également caractérisé les LT-CD8 PD-1+ TIM-3+ dans les lymphomes en combinant un marquage CD20 (quadruple + Dapi). Selon le type de lymphome, TIM-3 était coexprimé avec PD-1 à la surface des CD8 et plus ou moins au contact avec les cellules lymphomateuses CD20+. D'autre part, lorsque TIM-3 était coexprimé, les LT-CD8 étaient plus volontiers proliférant (comarquage Ki-67) en comparaison aux PD-1+ TIM-3-. Afin de poursuivre dans la caractérisation Th-1/IFN-gamma, j'ai élaboré la mise au point de la détection d'ARN dans les lymphocytes T in situ dans la tumeur, permettant de faire des liens avec leur fonctionnalité. Au total mes travaux de thèse ont permis de mettre en évidence des biomarqueurs immunologiques composites en lien avec l'expression des récepteurs inhibiteurs PD-1 et/ou TIM-3 et la perte de fonctionnalité (IFN-gamma) des lymphocytes T intratumorauxIt has been mainly described that the inhibitory receptors coexpression (PD-1, TIM-3, LAG-3, TIGIT) by lymphocytes in the tumor microenvironment (TME) induces a local immunosuppression. Targeting these receptors particularly PD-1 and its ligand PD-L1 is of great clinical benefit in cancer many types treatment (melanoma, renal and lung cancer in particular). In the most cases of cancer, like melanoma and lung cancer, a CD8-T cell and Th-1/IFN-gamma response is of good prognosis. But this is not the case in renal cancer and in hemopathies. My PhD work attempts to characterize clinical and biological implication of PD-1 and TIM-3 expression by intra-tumor lymphocytes in the setting of renal cancer and lymphoma. My PhD work has been conducted thanks to new methods of multiplexed characterization of the TME. Multispectral immunofluorescence lead to identify 7 parameters at the same time, and in this study I elaborated the identifications of lymphocytes markers in situ within the tumor: 4 membrane and/or nuclear proteins + nuclei (Dapi counterstain) and also coupled with the RNA detection. This tool allows me to accurately study the coexpression of PD-1 and TIM-3 at the CD8-T cell surface thanks to colocalisation identification and counting of these 3 markers. With the same method, I found that PD-L1 and Gal-9, which are PD-1 and TIM-3 ligands, were also expressed in the TME of renal carcinoma. I found that the coexpression of TIM-3 together with PD-1 in the CD8-T cells had a double relevance (i) at functional level, CD8-T cells were less able to secrete gamma-IFN (ii) at clinical level, patients harboring a higher infiltrate were more likely to relapse. The presence of PD-L1 and Gal-9 suggested interactions with inhibitory receptors of T cells. I also characterized CD8-T cells expressing PD-1 and TIM-3 in lymphomas, combining a CD20 staining (quadruple staining + Dapi). TIM-3 was more or less expressed depending of the lymphoma type near to CD20+ cells. TIM-3 PD-1 CD8-T cells were more likely Ki-67+ compared to TIM-3- cells, suggesting a more proliferative capacity. In order to continue the characterization of the Th-1/gamma-IFN-gamma immune response, I elaborate a technic to detect the gamma-IFN RNA in situ, together with lymphocytes staining, allowing the exploration of functionality within the tumor. To summarize, during my PhD work I could characterize composite immune biomarkers linked to the functionality of CD8-T cell and gamma-IFN Th-1 response
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Harwood, Reuben. "The response of tumour-infiltrating myeloid cells to the chemotherapy-treatment of tumours." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/6640/.
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Myeloid cells are a major component of most forms of malignant tumour. The plasticity of such cells means that they can alter their phenotype in response to changes in the tumour microenvironment, including the pronounced ones that take place after chemotherapy. Tumour cell death, as well as the various cytokines and chemokines released by cells in tumours after such treatments, are now known to alter both the recruitment and function of myeloid cells. Recent studies have shown that monocytes recruited into tumours during/following chemotherapy can promote tumour chemoresistance and metastasis. The data presented in this thesis suggest that, following chemotherapy, tumour-associated macrophages (TAMs) may increase their expression of the neutrophil-recruiting chemokines, CXCL1, CXCL2 and CXCL5, and possibly stimulate the intratumoural accumulation of neutrophils. Responding to these CXC chemokines (and possibly other secreted factors in chemotherapy-treated tumours), neutrophils may then upregulate their expression of such inflammatory cytokines as TNFα, CCL2 and CCL3. Furthermore, data from in vitro invasion assays suggest that neutrophil-derived TNFα is capable of inducing tumour cell invasiveness. Notably, the number of tumour-infiltrating neutrophils was significantly increased after chemotherapy in 3 of the 4 mouse tumour models used. Furthermore, in all 4 tumour models there were significantly more TNFα+ neutrophils after chemotherapy compared to control tumours. Combined treatment with chemotherapy and SB 265610, a CXCR2 antagonist that inhibits CXCL1, CXCL2 and CXCL5 signalling, successfully reduced both the number of these tumour-infiltrating, TNFα+ neutrophils, and the overall level of immunodetectable TNFα in tumours after chemotherapy. Although TNFα is known to be capable of supporting tumour growth, angiogenesis and metastasis, it remains to be seen whether such an increase in neutrophil TNFα expression contributes significantly to the post-chemotherapy regrowth of either primary or metastatic tumours. This could be achieved by giving chemotherapy to mice in which TNFα has been selectively knocked out/down in neutrophils. Data presented here suggest that combining chemotherapy with CXCR2 inhibitors like SB 265610 to inhibit the above neutrophil-mediated events could improve patient tumour responsiveness to chemotherapy and reduce tumour relapse.
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Bennett, Amy Kathleen. "Adenosine and breast cancer, effects on tumor cell growth and lymphocyte infiltration in a three-dimensional model of tumor tissue." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0017/MQ57195.pdf.
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Borgström, Annelie. "Analysis of tumour infiltrating leukocytes in colon cancer carcinoma in a syngeneic rat model." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-56910.
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Tumour immunity is a balance between immune mediators that promote tumor progression versus mediators that promote tumor rejection. Infiltrating lymphocytes in human colorectal cancer tissues are independent prognostic factors for a better survival and a high number of cytotoxic CD8+ T-cells have been associated with a better prognosis in terms of a longer and disease free survival for the patient. In our syngeneic rat model we induce colon carcinoma subperitoneally by injecting a colon cancer cell line BN7005, a cell line expressing the epitope (Lewis Y) for the BR96 antibody. Tumours are dissected out and treated with different fixatives and then either frozen, snap-frozen or embedded in paraffin followed by sectioning. Immunohistochemistry using monoclonal antibodies against the tumour infiltrating leukocytes was performed on the tissue. The results were seen as an infiltration of different leukocytes in the tumours.
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Girard, Pauline. "Pathophysiologie des pDCs et des Lymphocytes Tγδ en contexte de mélanome, et potentiel de leur interaction pour le développement de nouvelles thérapies The features of circulating and tumor-infiltrating gdT cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome Potent Bidirectional Cross-Talk Between Plasmacytoid Dendritic Cells and γδT Cells Through BTN3A, Type I/II IFNs and Immune Checkpoints." Thesis, Université Grenoble Alpes, 2020. http://www.theses.fr/2020GRALV042.
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.Les pDCs et Tγδ ont des rôles cruciaux dans l’initiation et l’orientation des réponses immunitaires. Leurs fonctions uniques, leur grande plasticité et leur capacité d’interagir avec de nombreux acteurs immunitaires leur permettent de créer un lien entre l’immunité innée et l’immunité adaptative. Elles contribuent donc grandement aux réponses immunitaires protectrices et pathogéniques, et sont de ce fait très prometteuses pour le développement d’immunothérapies anti-tumorales, autant en tant que vecteurs que cibles. Cependant, les lymphocytes Tγδ n’ont pas été étudiés de manière approfondie en contexte de mélanome, et les interactions entre pDCs et Tγδ n’ont été explicitées ni en contexte sain, ni en contexte mélanome, ou le contrôle immunitaire de la tumeur ‡ long terme est encore un défi. Nous avons réalisé une étude détaillée du phénotype et de la fonction des lymphocytes Tγδ circulant et infiltrant le mélanome, et analysé leur impact sur l’évolution clinique. Nous avons aussi caractérisé les interactions bidirectionnelles entre les pDCs et les Tγδ issus de sang de donneurs sains, et de sang ou de tumeur de patients. Nous avons mis en évidence que le mélanome détourne les fonctions effectrices des Tγδ dans le but d’échapper au contrôle immunitaire, et que les caractéristiques des Tγδ issus de sang ou de tumeurs de patients peuvent étre des bio-marqueurs prometteurs d’évolution clinique. Nous avons également montré que les interactions entre pDCs et Tγδ sont médiées par les IFNs de type I et II et par le récepteur BTN3A, essentiel pour l’activation des Td2+, et sont dérégulées en contexte de mélanome. L’administration de cytokines et d’anticorps ciblant les points de contrôle immunitaire peut rétablir des interactions fonctionnelles entre les deux populations cellulaires. De façon intéressante, nous avons observé une augmentation de l’expression de BTN3A sur les pDCs et Tγδ issus de sang de patients ou de tumeurs, tout en soulignant une potentielle dysfonction de cette molécule. Notre étude révèle que le mélanome détourne les interactions entre pDCs et Tgd notamment via la dérégulation de BTN3A. De tels résultats motivent l’exploitation de ces effecteurs immunitaires ainsi que de leur synergie, pour développer de nouvelles approches thérapeutiques exploitant leur potentiel anti-tumoral tout en évitant leur détournement par la tumeur pour améliorer l’évolution clinique des patients. Nos découvertes soutiennent l’exploitation de ces partenaires puissants et prometteurs pour élaborer de nouvelles stratégies thérapeutiques et restaurer des réponses immunes appropriées en contexte de cancer, infections et auto-immunitéBoth pDCs and γδT cells harbor critical roles in immune responses induction and orientation. Their unique features, high functional plasticity and ability to interact with many immune cell types allow them to bridge innate and adaptive immunity. They actively contribute to protective and pathogenic immune responses, which render them very attractive both as targets and vectors for cancer immunotherapy. Yet, γδT cells have not been extensively explored in melanoma, and despite strategic and closed missions, cross-talks between pDCs and γδT cells have not been deciphered yet, neither in healthy context nor in cancers, especially in melanoma where the long-term control of the tumor still remains a challenge. We provided here a detailed investigation of the phenotypic and functional properties of circulating and tumor-infiltrating γδT cells in melanoma patients, as well as their impact on clinical evolution. We also characterized the bidirectional cross-talks between pDCs and γδT cells both from healthy donor’s blood, patient’s blood and tumor micro-environment. Our study highlighted that melanoma hijacked γδT cells to escape from immune control, and revealed that circulating and tumor-infiltrating γδT cell features are promising potential biomarkers of clinical evolution. We also demonstrated crucial bidirectional interactions between these key potent immune players though type I and II IFN and BTN3A that are dysfunctional in the context of melanoma. Reversion of the dysfunctional bidirectional cross-talks in melanoma context could be achieved by specific cytokine administration and immune checkpoint targeting. We also revealed an increased expression of BTN3A on circulating and tumor-infiltrating pDCs and γδT cells from melanoma patients but stressed out its potential functional impairment.Thus, our study uncovered that melanoma hijacked pDCs/ γδT cells bidirectional interplay to escape from immune control, and pointed out BTN3A dysfunction. Such understanding will help harnessing and synergizing the power of these potent immune cells to design new therapeutic approaches exploiting their antitumor potential while counteracting their skewing by tumors to improve patient outcomes. Our findings pave the way to manipulate these potent and promising cell partners to design novel immunotherapeutic strategies and restore appropriate immune responses in cancers, infections and autoimmune diseases
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Johnson-Marshall, Alice Katherine. "Analysis of methylation level and expression of seven tumour-related genes in diffusely infiltrating astrocytomas." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620641.
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Oliveira, Claudia Teresa de [UNESP]. "Mielopatia infiltrativa por tumores não-hematológicos." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/88099.
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A infiltração de MO por tumores não-hematológicos tem sido descrita desde 1935 e, mais recentemente, desperta interesse da comunidade científica, pois inúmeros trabalhos têm relacionado a presença de células tumorais na MO com o processo de carcinogênese e a progressão tumoral. O presente estudo teve por objetivo o levantamento dos casos com diagnóstico de mielopatia infiltrativa por tumores nãohematológicos, provenientes da Faculdade de Medicina de Botucatu – UNESP e do Hospital Amaral Carvalho – Jaú, avaliados, retrospectivamente, no período de 1998 a 2008 (num universo de 15.191 coletas de MO). Incluímos 193 pacientes, dos quais 171 eram adultos e 22 crianças (idade ≤ 21 anos), com paridade entre os sexos (1:1) e mediana de idade de 55 anos. Foram analisados dados clínicos, diagnóstico e estadiamento do tumor primário, sítios de metástases, características laboratoriais (hemograma e marcadores tumorais séricos), características da MO, tratamento e a relação desses fatores com a sobrevida dos pacientes, através do programa de estatística SPSS®. Os resultados encontrados apontam que os tumores que mais frequentemente infiltraram a MO nos adultos foram: tumores de mama, próstata e sítio primário indeterminado, e neuroblastoma nas crianças. A análise da MO revelou positividade de 80% para mielograma e BMO, e presença de fibrose em 32% dos pacientes (40%, quando associados a áreas de necrose no mesmo material). Na avaliação hematológica observamos: anemia, alteração de leucócitos e plaquetopenia. Houve diferença, estatisticamente significante, com maior mediana de sobrevida global (p= 0,000) para pacientes do sexo feminino, portadores de adenocarcinoma de mama, em estádios iniciais e que receberam algum tipo de tratamento (quimio, radio e/ou hormonioterapia). Na análise de sobrevida, a partir do diagnóstico de mielopatia infiltrativa, houve...
Bone marrow (BM) infiltration by nonhematopoietic tumors has been described since 1935, and a increased number of papers about this topic have been published. Some of the studies have related the relationship between the presence of peripheral circulating tumors cells, bone marrow infiltration, carcinogenesis and tumor progression. This study has, as essential objective, the evaluation of infiltrative mielopathy by nonhematopoietic tumors from Faculdade de Medicina de Botucatu - UNESP and Hospital Amaral Carvalho – Jaú. Data were analised retrospectively from 1998 January to 2008 August (15.191 bone marrow samples). We have included 193 patients. One hundred seventy one were adults and 22 were children (considered age ≤ 21 years), with similar number of patients by gender, and median age 55 years. Medical records from the selected patients were analised, with focus on clinical aspects, primary site of tumor, initial stage, metastatic sites, hematologic and bone marrow features, treatment and the relationship between this data and survival. Results have demonstrated that most frequent solid tumors in adults were breast cancer, prostate cancer and undetermined primary site, and neuroblastoma among children. Bone marrow revealed infiltration in 80% of samples by myelogram and BM biopsy, and fibrosis in 32% (40% when associated with necrosis area). We observed anaemia, leukocyte alterations and thrombocytopenia as hematologic features. There were significant differences in global survival, wich was better among female patients, diagnosis of breast cancer, initial clinical stages and who has received any type of treatment (chemotherapy, radiotherapy and/or hormoniotherapy). When we analised survival since diagnosis of infiltrative mielopathy, adult patients with leucoeritroblastic reaction and trombocytopenia, and undetermined primary site tumors, melanoma or gastrointestinal tumors had... (Complete abstract click electronic access below)
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Väyrynen, J. (Juha). "Immune cell infiltration and inflammatory biomarkers in colorectal cancer." Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526206417.
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Abstract Colorectal cancer (CRC) is one of the most common malignancies and causes of cancer deaths in Finland. Increased number of tumor-infiltrating immune cells has been associated with improved survival in CRC. However, accurate, reproducible analysis methods, as well as better understanding of the interrelationships between different inflammatory markers would be important in order to establish a valuable prognostic and potentially predictive tool. In these studies, a computer-assisted method for the analysis of the densities of tumor-infiltrating immune cells and a quantitative method for the evaluation of CRC-associated lymphoid reaction (CLR) were adopted and validated. Utilizing the new methods, the inflammatory cell infiltration was characterized in independent groups of 418 (Cohort 1) and 149 (Cohort 2) CRC patients. Serum matrix metalloproteinase-8 (MMP-8) levels were measured in Cohort 2 and in a control group of 83 healthy age- and gender-matched controls. The automated cell counting method was found accurate and reproducible. In the tumor samples, there were high positive correlations between different types of immune cells, with the exception of mast cells and CD1a+ immature dendritic cells. High numbers of T cells predicted improved disease-free survival. High CLR density correlated with low tumor stage, but also with better survival regardless of stage. The median serum MMP-8 level of the patients was more than three times higher than that of the healthy controls. In conclusion, the present studies provide insight into the significance of various immune cell types and inflammatory markers in CRC and validate new methods for the analysis of immune cell infiltration in CRC. The results suggest that, especially, the densities of tumor-infiltrating T cells and CLR represent relevant prognostic indicators in CRC. Further studies are needed to evaluate the potential value of serum MMP-8 as an aid for CRC diagnostics, surveillance, or prognosticationTiivistelmä Kolorektaalisyöpä on yksi yleisimmistä pahanlaatuisista kasvaintaudeista ja syöpäkuolemien aiheuttajista Suomessa. Tulehdussolujen korkean määrän kasvainnäytteissä on havaittu olevan yhteydessä potilaiden parempaan ennusteeseen. Tarkat ja luotettavat analyysimenetelmät sekä tieto eri tulehdusmerkkiaineiden keskinäisistä yhteyksistä olisivat tärkeitä, jotta tulehdussolukon määritystä voitaisiin luotettavasti käyttää potilaiden ennusteen arviointiin. Tutkimuksessa otettiin käyttöön ja validoitiin uusi tietokonepohjainen menetelmä kasvaimen tulehdussolukon arviointiin sekä uusi menetelmä kolorektaalisyövän imukeräsreaktion arviointiin. Kasvainnäytteiden tulehdussolukon määrää ja laatua analysoitiin itsenäisissä 418 (Kohortti 1) ja 149 (Kohortti 2) kolorektaalisyöpäpotilaan aineistoissa uusia menetelmiä hyödyntäen. Lisäksi kohortilta 2 sekä 83 terveeltä ikä- ja sukupuolivalikoidulta verrokilta määritettiin seerumin matriksin metalloproteinaasi-8 (MMP-8) -taso. Tietokonepohjaisen kuva-analyysin tarkkuus ja toistettavuus todettiin erinomaiseksi. Kasvainnäytteistä analysoitujen tulehdussolutyyppien määrät olivat riippuvaisia toisistaan mast-soluja ja CD1a+ epäkypsiä dendriittisoluja lukuun ottamatta. T-solujen runsas määrä oli yhteydessä taudin vähäisempään uusiutumisriskiin. Korkea imukerästiheys kasvainnäytteissä oli yhteydessä matalaan levinneisyysasteeseen sekä potilaiden parempaan ennusteeseen levinneisyysasteesta riippumatta. Seerumin MMP-8-tason mediaani oli potilailla yli kolme kertaa korkeampi kuin terveillä verrokeilla. Tutkimus tuo lisätietoa eri tulehdussolutyyppien ja tulehdusmerkkiaineiden merkityksestä kolorektaalisyövässä, ja sen tuloksena validoitiin uusia tulehdussolukon analysointimenetelmiä. Tulosten perusteella erityisesti kasvaimen alueen T-solujen ja imukerästen tiheys tuovat hyödyllistä tietoa potilaiden ennusteesta. Lisätutkimuksia tarvitaan seerumin MMP-8:n mahdollisesta soveltuvuudesta kolorektaalisyövän diagnostiikan, seurannan tai ennusteen määrittämisen apuvälineeksi
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Oliveira, Claudia Teresa de. "Mielopatia infiltrativa por tumores não-hematológicos /." Botucatu : [s.n.], 2009. http://hdl.handle.net/11449/88099.
Full textAbstract:
Orientador: Lígia Niero-MeloBanca: Lucilene Silva Ruiz e Rezende
Banca: Eduardo Moreira de Queiroga
Resumo: A infiltração de MO por tumores não-hematológicos tem sido descrita desde 1935 e, mais recentemente, desperta interesse da comunidade científica, pois inúmeros trabalhos têm relacionado a presença de células tumorais na MO com o processo de carcinogênese e a progressão tumoral. O presente estudo teve por objetivo o levantamento dos casos com diagnóstico de mielopatia infiltrativa por tumores nãohematológicos, provenientes da Faculdade de Medicina de Botucatu - UNESP e do Hospital Amaral Carvalho - Jaú, avaliados, retrospectivamente, no período de 1998 a 2008 (num universo de 15.191 coletas de MO). Incluímos 193 pacientes, dos quais 171 eram adultos e 22 crianças (idade ≤ 21 anos), com paridade entre os sexos (1:1) e mediana de idade de 55 anos. Foram analisados dados clínicos, diagnóstico e estadiamento do tumor primário, sítios de metástases, características laboratoriais (hemograma e marcadores tumorais séricos), características da MO, tratamento e a relação desses fatores com a sobrevida dos pacientes, através do programa de estatística SPSS®. Os resultados encontrados apontam que os tumores que mais frequentemente infiltraram a MO nos adultos foram: tumores de mama, próstata e sítio primário indeterminado, e neuroblastoma nas crianças. A análise da MO revelou positividade de 80% para mielograma e BMO, e presença de fibrose em 32% dos pacientes (40%, quando associados a áreas de necrose no mesmo material). Na avaliação hematológica observamos: anemia, alteração de leucócitos e plaquetopenia. Houve diferença, estatisticamente significante, com maior mediana de sobrevida global (p= 0,000) para pacientes do sexo feminino, portadores de adenocarcinoma de mama, em estádios iniciais e que receberam algum tipo de tratamento (quimio, radio e/ou hormonioterapia). Na análise de sobrevida, a partir do diagnóstico de mielopatia infiltrativa, houve... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Bone marrow (BM) infiltration by nonhematopoietic tumors has been described since 1935, and a increased number of papers about this topic have been published. Some of the studies have related the relationship between the presence of peripheral circulating tumors cells, bone marrow infiltration, carcinogenesis and tumor progression. This study has, as essential objective, the evaluation of infiltrative mielopathy by nonhematopoietic tumors from Faculdade de Medicina de Botucatu - UNESP and Hospital Amaral Carvalho - Jaú. Data were analised retrospectively from 1998 January to 2008 August (15.191 bone marrow samples). We have included 193 patients. One hundred seventy one were adults and 22 were children (considered age ≤ 21 years), with similar number of patients by gender, and median age 55 years. Medical records from the selected patients were analised, with focus on clinical aspects, primary site of tumor, initial stage, metastatic sites, hematologic and bone marrow features, treatment and the relationship between this data and survival. Results have demonstrated that most frequent solid tumors in adults were breast cancer, prostate cancer and undetermined primary site, and neuroblastoma among children. Bone marrow revealed infiltration in 80% of samples by myelogram and BM biopsy, and fibrosis in 32% (40% when associated with necrosis area). We observed anaemia, leukocyte alterations and thrombocytopenia as hematologic features. There were significant differences in global survival, wich was better among female patients, diagnosis of breast cancer, initial clinical stages and who has received any type of treatment (chemotherapy, radiotherapy and/or hormoniotherapy). When we analised survival since diagnosis of infiltrative mielopathy, adult patients with leucoeritroblastic reaction and trombocytopenia, and undetermined primary site tumors, melanoma or gastrointestinal tumors had... (Complete abstract click electronic access below)
Mestre
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Morrone, Luigi. "The Influence of 3D Cell Organization in Tumor Spheroid on Natural Killer Cell Infiltration and Migration." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-286605.
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Natural Killer cells are a type of lymphocyte belonging to the innate immune system and they operate cell-mediated cytotoxicity and release of pro-inflammatory cytokines against cancerous cells. However, in vivo testings have shown a reduced activity of NK cells against solid tumors probably due to the negative influence of the immunosuppressive tumor microenvironment. Multicellular tumor spheroids may constitute an advantageous model in cancer biology for studying the mechanisms behind cancer immune editing since it more closely mimics the complexity of the human body compared with the 2D model counterpart. This study investigated the interaction between NK cells isolated from blood and tumor spheroids obtained from A498 renal carcinoma cells, using light-sheet microscopy imaging which allows satisfactory cell tracking in the inner layers of the spheroids. NK cells not only indeed interact with tumor spheroids, but many of them were able to penetrate the spheroids inducing some changes in the structure of the latter. NK cells were also tracked over time, displaying the migration path and calculating the speed. The fluorescence intensity of the NK cells was found reduced as soon as they penetrate the spheroid but, conversely, the speed seems to increase inside the spheroid, a possible sign of the fallibility of the tracking algorithm in this specific case. We propose solutions for more sophisticated future implementations, involving the use of marks during the experimental phase and drift corrections at the data analysis level.
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Shi, Zheng Isabelle. "Prolifération et capacité cytotoxique des lymphocytes T infiltrant les tumeurs induites par les cellules malignes autologues de lymphomes B : étude de 85 clones T issus de 9 patients." Université Joseph Fourier (Grenoble ; 1971-2015), 1994. http://www.theses.fr/1994GRE10215.
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Les til-t provenant de 20 lmnh b de type histologique/cytologique varies ont été étudiés et 174 clones t ont été générés dans 9 des cas. 4 groupes prolifératifs ont été identifiés sur la base de prolifération des til-t. Les pourcentages de clones proliférant dans ces 4 groupes sont respectivement de 63%, 70% et 56%, et 10%. Dans les lmnh de forte malignite, 25% (5/20) des clones t prolifèrent sous l'effet des bm alors que dans les lmnh de faible malignite, il y en a 55% (36/65) (p < 0,05). Il en est de même pour leurs capacités de dissémination : dans les lmnh localisés (stades i et ii), 70% (28/40) des clones t prolifèrent au contact des bm, alors que dans les lmnh disséminés (stades iii et iv), 29% (13/45) des clones t ont cette capacité. La différence apparaît encore plus significative (p < 0,01). Ces corrélations ne sont pas observées avec la stimulation par les cellules b normales autologues infectées par le virus epstein barr (b-ebv) ou les cellules b normales allogeniques (bn-allo). La réponse proliférative des clones t vis-à-vis des bm n'est pas corrélée à un phénotype préférentiel des clones t cd4 ou cd8. 46 clones t provenant de 8 ganglions malins ont été testés pour leur capacité cytotoxique contre les bm. Seuls 6 clones t ont exprimé cette propriété. La production de gm-csf, d'inf, de tnf et d'il4 sur 9 clones, et celle d'il2 sur 5 clones ont été détectées sous l'effet des bm. Des clones t sont capables de proliférer et/ou d'exprimer l'ag cd25 au contact des bm, avec une intensité proportionnelle à la quantité de cellules b utilisées. La prolifération et l'expression de l'ag cd25 des cellules t est liée à une structure membranaire des bm. 6 clones t sont incapables de proliférer au contact des b-ebv et des bn-allo, ce qui est très en faveur de l'existence d'un antigène stimulant propre aux bm. En utilisant la méthode des ac bloquants, nous avons démontré que des clones t prolifèrent au contact des bm selon deux mécanismes qui impliquent tous le tcr mais qui se différencient par l'intervention ou non du cmh des bm
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Sun, Roger. "Utilisation de méthodes radiomiques pour la prédiction des réponses à l’immunothérapie et combinaisons de radioimmunothérapie chez des patients atteints de cancers Radiomics to Assess Tumor Infiltrating CD8 T-Cells and Response to Anti-PD-1/PD-L1 Immunotherapy in Cancer Patients: An Imaging Biomarker Multi-Cohort Study Imagerie médicale computationnelle (radiomique) et potentiel en immuno-oncologie Radiomics to Predict Outcomes and Abscopal Response of Cancer Patients Treated with Immunotherapy Combined with Radiotherapy Using a Validated Signature of CD8 Cells." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL023.
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Depuis l’arrivée des inhibiteurs de points de contrôle immunitaire, l’immunothérapie a profondément modifié la prise en charge de nombreux cancers, permettant parfois des réponses tumorales prolongées chez des patients atteints de cancers aux stades très avancés. Cependant, malgré des progrès thérapeutiques constants et des associations de traitements combinant par exemple radiothérapie et immunothérapie, la majorité des patients traités ne présentent pas de bénéfices à ces traitements. Ceci explique l’importance de la recherche de biomarqueurs innovants de réponse à l’immunothérapie.L’application de l’intelligence artificielle en imagerie est une discipline récente et en pleine expansion. L’analyse informatique de l’image, appelée également radiomique, permet d’extraire des images médicales de l’information non exploitable à l’œil nu, potentiellement représentative de l’architecture des tissus sous-jacents et de leur composition biologique et cellulaire, et ainsi de développer des biomarqueurs grâce à l’apprentissage automatique (« machine learning »). Cette approche permettrait d’évaluer de façon non invasive la maladie tumorale dans sa globalité, avec la possibilité d’être répétée facilement dans le temps pour appréhender les modifications tumorales survenant au cours de l’histoire de la maladie et de la séquence thérapeutique.Dans le cadre de cette thèse, nous avons évalué si une approche radiomique permettait d’évaluer l’infiltration tumorale lymphocytaire, et pouvait être associée à la réponse de patients traités par immunothérapie. Dans un deuxième temps, nous avons évalué si cette signature permettait d’évaluer la réponse clinique de patients traités par radiothérapie et immunothérapie, et dans quelle mesure elle pouvait être utilisée pour évaluer l’hétérogénéité spatiale tumorale. Les défis spécifiques posés par les données d’imagerie de haute dimension dans le développement d’outils prédictifs applicables en clinique sont discutés dans cette thèseWith the advent of immune checkpoint inhibitors, immunotherapy has profoundly changed the therapeutic strategy of many cancers. However, despite constant therapeutic progress and combinations of treatments such as radiotherapy and immunotherapy, the majority of patients treated do not benefit from these treatments. This explains the importance of research into innovative biomarkers of response to immunotherapyComputational medical imaging, known as radiomics, analyzes and translates medical images into quantitative data with the assumption that imaging reflects not only tissue architecture, but also cellular and molecular composition. This allows an in-depth characterization of tumors, with the advantage of being non-invasive allowing evaluation of tumor and its microenvironment, spatial heterogeneity characterization and longitudinal assessment of disease evolution.Here, we evaluated whether a radiomic approach could be used to assess tumor infiltrating lymphocytes and whether it could be associated with the response of patients treated with immunotherapy. In a second step, we evaluated the association of this radiomic signature with clinical response of patients treated with radiotherapy and immunotherapy, and we assessed whether it could be used to assess tumor spatial heterogeneity.The specific challenges raised by high-dimensional imaging data in the development of clinically applicable predictive tools are discussed in this thesis
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Sektioglu, Ibrahim Murathan [Verfasser], and Günter J. [Akademischer Betreuer] Hämmerling. "Control of T cell infiltration and tumor rejection by regulatory T cells, basophils and macrophages / Ibrahim Murathan Sektioglu ; Betreuer: Günter J. Hämmerling." Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/1180500407/34.
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Gao, Jingfang. "Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer." Doctoral thesis, Linköping : Univ, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-10516.
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Venkatesh, Amritha K. "Toll-like Receptor 3 Signaling in Breast Cancer Cells and the Recruitment of Leukocytes to the Tumor Microenvironment." Ohio University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1339093424.
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Oguejiofor, Kenneth Kenechukwu. "Prognostic markers in oropharyngeal cancers." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/prognostic-markers-in-oropharyngeal-cancers(fda96224-657d-4049-ae6c-50db33a5388a).html.
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Introduction: Human papillomavirus (HPV) is changing the prevalence, survival and treatment paradigms in oropharyngeal squamous cell carcinoma (OPSCC). Improved survival of patients with HPV positive compared to HPV negative OPSCC has led to trials of treatment de-escalation. Current HPV detection methods are imprecise, therefore standardised assessment of transcriptionally active HPV in OPSCC is required. Furthermore, the differences in immune characteristics and/or the hypoxia response/effects could explain observed differences in prognosis between HPV positive and negative OPSCC. Rigorous HPV detection and subsequent biomarker evaluation should provide additional information required before introduction of treatment de-escalation in broad patient groupings. Methods: The study cohort was 218 patients with OPSCC who received radiotherapy with curative intent. HPV status was determined on pre-treatment, formalin-fixed paraffin-embedded blocks using: 1) polymerase chain reaction (PCR); 2) in-situ hybridisation (ISH) and 3) immuno-histochemistry (IHC). QuantiGene multiplex assay was designed to detect mRNA of reference sequences of the common high-risk HPV types (16, 18, 33, 35, 45, 52 and 58). HPV detection methods were compared with mRNA quantification. Multimarker IHC of immune cell markers using chromogenic and fluorescent staining was performed, analysed and compared with single marker IHC using automated multispectral image analysis. A validated multiplex IHC method was used for a) chromogenic (CD3, CD4, CD8, and FoxP3) and b) fluorescent (CD8, CD68 and PD1/PD-L1) evaluation in tumour and stroma compartments. Single marker IHC was used to investigate tumour hypoxia markers (HIF-1α and CA-IX) in HPV positive and negative OPSCC. Results: p16 IHC and ISH were the most sensitive and specific, respectively, for classifying HPV status. The combination of the three tests had the highest positive/negative predictive values compared with QuantiGene mRNA detection. Multiplex validation showed that, for serial sections up to 6 μm apart, there were highly significant correlations (P<0.0001) between single and multiplex counts for both chromogenic and fluorescent IHC. Overall there was less variation in cell counts with fluorescent staining when compared to chromogenic staining. Multiplex IHC of TILs in HPV positive and negative OPSCC showed higher infiltration in both tumour and stromal areas of CD3+CD4+ and CD3+CD8+ T cells but not CD4+FoxP3 Tregs in HPV positive compared with HPV negative OPSCC. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). PD-L1 expression was higher in HPV negative OPSCC and this was related to macrophage (CD68) expression of PD-L1. In HPV negative tumours infiltration with CD68+PD-L1 was associated with a good prognosis. HPV negative patients had higher expression of HIF-1α but not CA-IX. High expression of both markers was associated with a poor prognosis irrespective of HPV status. Conclusions: There are other prognostic factors operating in the larger subdivision of HPV positive and negative OPSCC. Precise HPV detection and inclusion of other prognostic factors is required before treatment de-escalation is used. Expression of immune inhibitory factors (PD1/PD-L1) alone without contextualisation with immune cell density is insufficient for patient prognostication and potential selection for therapy using immune checkpoint inhibitors. Hypoxia modification of radiotherapy should be explored in both HPV positive and negative OPSCC.
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Eerola, A. K. (Anna-Kaisa). "Apoptosis and apoptosis regulating proteins and factors in small and large cell lung carcinoma." Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514254066.
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Abstract
Aptosis denotes a biochemically and morphologically distinct
chain of events leading to self-destruction of cell. It is pivotal
in the maintenance of tissue homeostasis and also plays a role in neoplasm.
In this work, the extent of apoptosis and apoptosis regulating proteins
and factors was studied in a total of 94 patients operated for lung
carcinoma, including 56 small cell lung carcinomas (SCLC) and 38
large cell lung carcinomas (LCLC). The extent of apoptosis was determined
by detecting and counting the relative and absolute numbers of apoptotic
cells and bodies using 3'- end labelling of the apoptotic
DNA. The extent of apoptosis in SCLC was compared with the cell proliferation
activity as determined by Ki-67 immunohistochemistry, with the volume
density of necrosis and with the occurrence of immunohistochemically
detectable p53 and bcl-2 proteins. In order to test the hypothesis
that increased apoptotic activity is connected with neuroendocrine differentiation
and with low differentiation degree in LCLC and that it is regulated
by bcl-2 family proteins, the extent of apoptosis and tumour necrosis
was analysed in relation to the expression of bcl-2 family proteins
bcl-2, mcl-1, bax and bak. Apoptosis, tumour infiltrating lymphocytes
(TILs), and angiogenesis are important factors that contribute to
tumour growth. In the present study immunohistochemical methods
were used to investigate the relationships of these factors and
their role in the prognosis of the patients with LCLC and SCLC.
A remarkably high apoptotic activity was detected in both
SCLC and LCLC. The mean apoptotic index in SCLC was 2.70 % and
in LCLC 2.49 %. Exceptionally high proliferation activity
and high percentage of tumour necrosis was seen in SCLC. 58 % of
SCLC showed more than 40 % of Ki-67 positive nuclei, and
tumour necrosis was seen in 83 % of the cases. P53 protein
accumulation was detected in 38 % and bcl-2 expression
in 50 % of SCLC. The extent of apoptosis in SCLC was inversely
related to tumour necrosis and p53 protein accumulation. In LCLC,
bcl-2 expression was detected in 40 % of the cases. It
was associated with neuroendocrine differentiation and predicted favourable
prognosis of the patients. A high number of T cells and macrophages
with a small number of B cells was detected in both SCLC and LCLC.
The occurrence of intratumoural cytotoxic CD8 cells was associated
with the occurrence of apoptotic bodies in SCLC. The increased number
of intratumoural T cells, CD8-positive cells and macrophages predicted
favourable prognosis of the patients with SCLC. In LCLC, an increased
number of B cells and macrophages, but not T cells, was associated
with better survival.
Iaddition to tumour cells, numerous apoptotic bodies could
also be found within alveolar macrophages within and close to tumour
tissue. In order to test whether such cells could be found in sputum
smears and if their presence could be utilised as a marker of malignancy
in tumour diagnosis, the occurrence of alveolar macrophages with
apoptotic bodies (AMWABs) was analysed in 84 sputum samples and
13 broncho-alveolar lavage (BAL) specimens from patients with and
without lung carcinoma. AMWABs could be found in cytological samples
of the patients with lung carcinoma. In sputum and BAL specimens,
enhanced apoptosis, as measured by an increased number of AMWABs
reflected and was indicative of malignancy. This was also true for
cytological specimens of the patients even when the actual malignant
cells were not found. Therefore the AMWABs served as a marker of
pulmonary malignancy.
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Régnier, Paul. "Effet des interactions homéostatiques entre cellules dendritiques, lymphocytes effecteurs et régulateurs sur les réponses immunitaires anti-tumorales : étude du rôle de différentes cellules dendritiques in vivo chez la souris, et étude algorithmique des relations complexes entre transcriptome tumoral, populations immunitaires et survie in silico chez les patients A paradoxical role for Flt3 ligand in tumor immune response reveals homeostatic control of NK and treg cells by dentritic cells Tumor infiltration by immune cells favors patient survival in some cancers bur is highly detrimental in immune-privileged sites." Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2244&f=15657.
Full textAbstract:
Le cancer, l'une des principales causes de décès dans le monde, peut apparaître dans presque tout type de tissu, et est caractérisé par la prolifération anarchique de cellules et l'établissement d'une réponse immunitaire tolérogène favorisant la croissance tumorale, rendant souvent toute intervention médicamenteuse peu efficace. Les cellules dendritiques (DCs), véritables sentinelles de l'organisme, semblent jouer un rôle dans l'établissement à la fois d'une réponse anti-tumorale efficace et d'une tolérance face au cancer. Malgré tout, le rôle des différents sous-types de DCs dans le développement tumoral reste mal connu. Au cours de cette thèse, j'ai étudié différents acteurs cellulaires dendritiques et lymphocytaires, leurs relations et leur implication dans la réponse ou la tolérance immunitaire aux tumeurs. Durant la première partie de ma thèse, j'ai abordé l'effet de la modulation artificielle de l'homéostasie des DCs sur les autres cellules immunitaires ainsi que sur la réponse anti-tumorale in vivo chez la souris. J'ai montré qu'il existait un rôle paradoxal de la cytokine Flt3-L (FL) - un facteur de croissance essentiel à la différentiation et à l'homéostasie des DCs dites classiques/conventionnelles (cDCs) et des DCs plasmacytoïdes (pDCs) - sur la croissance du mélanome B16. En effet, sa surexpression ou son absence mènent à un meilleur contrôle du développement tumoral, accompagnées par une survie accrue des souris. L'absence de FL induit, en sus d'une disparition des cDCs et pDCs, une réduction drastique des lymphocytes T régulateurs (Tregs) protégeant la tumeur, ainsi qu'un renforcement général de la réponse immunitaire anti-tumorale adaptative via les lymphocytes T helpers. Sa surexpression induit une augmentation du nombre de cDCs et pDCs, et malgré une présence accrue de Tregs, un fort recrutement intra-tumoral de lymphocytes natural killer (NK) activés, un des acteurs majeurs de la réponse anti-tumorale innée. L'étude de souris déficientes en cDCs m'a également permis de démontrer l'existence d'un contrôle de l'homéostasie des NK par les DCs. De plus, la combinaison d'un traitement par FL et un anticorps déplétant les Tregs a un effet thérapeutique exacerbé chez la souris. Ensuite, par l'analyse bio-informatique de transcriptomes provenant de 35 types de cancers différents, j'ai montré que le paradoxe du FL existe également chez l'Homme, du moins pour certains cancers, et que les signatures géniques spécifiques de sous-populations de DCs peuvent être corrélées de manière paradoxale, bénéfique ou préjudiciable à la survie. En parallèle, j'ai évalué la présence de diverses cellules immunitaires dans l'infiltrat tumoral et leurs effets sur la survie des patients. Grâce aux algorithmes en langage R que j'ai développés, j'ai pu analyser pour tous les cancers étudiés les signatures géniques spécifiques de populations cellulaires immunitaires ainsi que les gènes et fonctions biologiques (pathways) les plus fortement dysrégulés ou impliqués dans le contrôle de la survie à 5 ans. Les résultats indiquent que les cellules immunitaires de l'infiltrat tumoral dans leur ensemble peuvent jouer, selon le cancer, un rôle bénéfique ou délétère. Cet infiltrat et les pathways immunitaires associés se sont révélés généralement de mauvais pronostic dans les cancers des organes dits immuno-privilégiés, mais en revanche bénéfiques dans les cancers du sein et de la peau. Pour chaque type de cancer, j'ai déterminé l'impact individuel sur la survie de différents types de cellules immunitaires et ai établi les corrélations entre les pathways impliqués et certaines de ces populations cellulaires. L'ensemble de ces résultats permet de mieux comprendre les relations complexes entre chaque cancer et son infiltrat cellulaire, et permettra à terme d'aider à développer des stratégies immuno-thérapeutiques plus adaptées à un environnement tumoral donné, en ciblant les populations immunitaires pouvant réellement impacter la survie des patientsThe cancer, one of the main causes of death in the world, can appear in almost any type of tissue, and is characterized by an anarchic proliferation of cells and the establishment of a tolerogenic immune response favouring the tumour growth, leading to low efficiency of drug interventions. Dendritic cells (DCs), real sentinels of the body, seem to play a role in the establishment of both efficient anti-tumoral immune response and tolerance against cancer. Nevertheless, the role of the different DCs subtypes in the tumoral development stays poorly known. During this thesis, I studied different dendritic and lymphocytic cellular actors, their relationships and their involvement in the immune response or tolerance to tumours. During the first part of my thesis, I studied the effect of the artificial modulation of DCs homeostasis on other immune cells and also on anti-tumoral response in vivo in mice. I proved the existence of a paradoxical role of the Flt3-L (FL) cytokine - a growth factor essential to the differentiation and the homeostasis of classical/conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) - on the B16 melanoma growth. In fact, its overexpression or absence both lead to a better control of the tumoral development, accompanied by an increased survival of mice. FL deficiency induces, together with the loss of both cDCs and pDCs, a drastic reduction of regulatory T lymphocytes (Tregs) protecting the tumour, and also a global reinforcement of the anti-tumoral adaptive immune response via helper T lymphocytes. Its overexpression induces an increase of the numbers of cDCs and pDCs, and despite a raised presence of Tregs, also a strong intra-tumoral recruitment of activated natural killer (NK) cells, one of the major actors of the anti-tumoral innate response. The study of cDCs-deficient mice allowed me to demonstrate the existence of a DCs-mediated control of the NK cells homeostasis. Furthermore, the combination of both FL treatment and antibody-mediated Tregs depletion has an exacerbated therapeutic effect in mice. Next, using bioinformatic analysis of transcriptomes of 35 different cancer types, I showed that the FL paradox also exists in humans, at least for some cancers, and that gene signatures specific of DCs subsets can be correlated in a paradoxical, beneficial or detrimental manner to survival. In parallel, I evaluated the presence of several immune cells in the tumour infiltrate and their effects on patients survival. Thanks to R language algorithms I developed, I was able to analyse for each studied cancer the immune cell populations-specific gene signatures and the most involved or dysregulated genes and biological functions (pathways) in the control of the 5 years survival of patients. My results indicate that the immune cells of the tumour infiltrate can play, according to the cancer, a beneficial or deleterious role. This immune infiltrate and the associated pathways were generally of bad prognosis in cancers of immune-privileged organs, but on the other hand were beneficial in skin and breast cancers. For each cancer type, I determined the individual impact on survival of several types of immune cells and established correlations between involved pathways and some of these cell populations. Altogether, the results allow to better understand the complex relationships between each cancer and the associated immune infiltrate, and will later lead to help the development of immunotherapeutic strategies more adapted to a given tumour environment, by targeting the immune populations that could really impact the survival of patients