Journal articles: 'Tumor Infiltrating'

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Rodin, William Carl Ivar, Patrik Sundström, Filip Ahlmanner, Elinor Bexe Lindskog, and Marianne Quiding Järbrink. "Potent anti-tumor effector functions in tumor-infiltrating MAIT and γδ T cells isolated from colon cancer patients." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 138.13. http://dx.doi.org/10.4049/jimmunol.202.supp.138.13.

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Abstract In colon cancer, tumor progression and patient outcome is affected by the cytokine balance in the tumors. IFNγ, TNFα and Granzyme B expression are associated with favorable patient outcome, while high IL-17 expression is associated with accelerated tumor progression. However, knowledge of the regulation and activation of unconventional T cell subsets in colon tumors is limited. The aim of this study was to characterize unconventional T cells in colon tumors and unaffected tissue, determine their capacity to produce cytokines affecting tumor progression as well as the In vitro cytotoxic capabilities of MAIT and γδ T cells. Using flow cytometry, we show that MAIT cells accumulate in colon tumors and that the frequencies of γδ T cells are reduced in the tumor epithelium. Using polyclonal stimulation, we show that IFNγ production by tumour infiltrating MAIT cells is impaired whilst tumour infiltrating γδ T have an increased expression of IFNγ, TNFα and Granzyme B. IL-17 expression was also elevated in tumour infiltrating γδ T cells, but at lower levels than the TH1 - associated cytokines. Tumor infiltrating MAIT cells had an exhausted (PD-1highTim-3+) phenotype compared to MAIT cells from unaffected tissue. Analyzing cytokine expression, we show that while no single molecule is lost the polyfunctional capacity of tumour infiltrating MAIT cells is decreased compared to MAIT cells from unaffected tissue. Altogether, this study shows that γδ T cells and MAIT cells contribute to the cytokine balance in colon tumors with a TH1 – dominated profile and that they have potent cytotoxic capacity, which may reduce tumor progression and improve patient outcome.

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Wirth, Thomas, Farizan Ahmad, Agnieszka Pacholska, Haritha Samaranayake, and Seppo Ylä-Herttuala. "The Syngeneic BT4C Rat Malignant Glioma is a Valuable Model to study Myelomonocytic cells in Tumors." Cancer Growth and Metastasis 5 (January 2012): CGM.S9314. http://dx.doi.org/10.4137/cgm.s9314.

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Background The impact of infiltrating macrophages on tumor progression in malignant gliomas has been studied extensively. However, there is a lack of animal models for studying the role of infiltrating macrophages in malignant gliomas. Material and methods: The BT4C rat malignant glioma model was characterized by immunohistochemical analysis of inflammatory cell types associated with the tumors. Results BT4C malignant gliomas are highly vascularized tumors with an infiltrative behavior. BT4C gliomas demonstrated a high infiltration rate of macrophages. Particularly, a CD68/VEGFR-1 positive subtype of macrophages was detected at the edges of malignant gliomas. Also, CD133 positive cells were located mainly at the infiltrative edges of gliomas, whereas VEGFR-2 was highly expressed throughout the malignant glioma. Conclusion The immunocompetent BT4C rat malignant glioma model shows features similar to its human counterpart, which makes it a valuable model to study the impact of tumor associated macrophages in the pathology of malignant gliomas.

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Whiteside, Theresa L., Lorenz M. Jost, and Ronald B. Herberman. "Tumor-infiltrating lymphocytes." Critical Reviews in Oncology/Hematology 12, no. 1 (January 1992): 25–47. http://dx.doi.org/10.1016/1040-8428(92)90063-v.

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Besser, Michal J., Ronnie Shapira-Frommer, and Jacob Schachter. "Tumor-Infiltrating Lymphocytes." Cancer Journal 21, no. 6 (2015): 465–69. http://dx.doi.org/10.1097/ppo.0000000000000154.

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Oliver, Gary, John Yannelli, and Diane Solomon. "Tumor-Infiltrating Lymphocytes." Acta Cytologica 40, no. 4 (1996): 691–94. http://dx.doi.org/10.1159/000333941.

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Mantovani, Alberto, and Robert Evans. "Tumor-infiltrating leukocytes." Immunology Today 6, no. 5 (May 1985): 144–45. http://dx.doi.org/10.1016/0167-5699(85)90134-3.

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Torcellan, Tommaso, Henry R. Hampton, Jacqueline Bailey, Michio Tomura, Robert Brink, and Tatyana Chtanova. "In vivo photolabeling of tumor-infiltrating cells reveals highly regulated egress of T-cell subsets from tumors." Proceedings of the National Academy of Sciences 114, no. 22 (May 15, 2017): 5677–82. http://dx.doi.org/10.1073/pnas.1618446114.

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Immune therapy is rapidly gaining prominence in the clinic as a major weapon against cancer. Whereas much attention has been focused on the infiltration of tumors by immune cells, the subsequent fate of these infiltrates remains largely unexplored. We therefore established a photoconversion-based model that allowed us to label tumor-infiltrating immune cells and follow their migration. Using this system, we identified a population of tumor-experienced cells that emigrate from primary tumors to draining lymph nodes via afferent lymphatic vessels. Although the majority of tumor-infiltrating cells were myeloid, T cells made up the largest population of tumor-egressing leukocytes. Strikingly, the subset composition of tumor-egressing T cells was greatly skewed compared with those that had infiltrated the tumor and those resident in the draining lymph node. Some T-cell subsets such as CD8+ T cells emigrated more readily; others including CD4−CD8− T cells were preferentially retained, suggesting that specific mechanisms guide immune cell egress from tumors. Furthermore, tumor-egressing T cells were more activated and displayed enhanced effector function in comparison with their lymph node counterparts. Finally, we demonstrated that tumor-infiltrating T cells migrate to distant secondary tumors and draining lymph nodes, highlighting a mechanism whereby tumor-experienced effector T cells may mediate antitumor immunity at metastatic sites. Thus, our results provide insights into migration and function of tumor-infiltrating immune cells and the role of these cells in tumor immunity outside of primary tumor deposits.

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Ho-Tin-Noe, Benoit H., Carla Carbo, Melanie Demers, Stephen M. Cifuni, Tobias Goerge, and Denisa D. Wagner. "Platelets Protect Tumors from Hemorrhage Induced by Stroma-Infiltrating Leukocytes." Blood 112, no. 11 (November 16, 2008): 3916. http://dx.doi.org/10.1182/blood.v112.11.3916.3916.

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Abstract In a recent study, we showed that platelets are crucial regulators of tumor vascular homeostasis in that they continuously prevent tumor hemorrhage through secretion of their granules. However, it remains unclear what platelets target to prevent tumor bleeding. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. We hypothesized that platelets protect tumors from vascular damages induced by infiltrating inflammatory cells. Here, we report that thrombocytopenia-induced tumor hemorrhage preferentially occurs at the periphery of tumors, where massive accumulation of monocytes/macrophages and neutrophils was revealed by tumor histology. To further investigate the role of tumor-infiltrating leukocytes in the induction of tumor hemorrhage in thrombocytopenic mice, we used genetically-engineered mice with a deficiency in either beta2 or beta3 integrins, or in integrin activation. We show that these mice have decreased leukocyte infiltration in the tumor stroma and are protected from thrombocytopenia-induced tumor hemorrhage. Using a model of TNFa-induced skin inflammation, we demonstrate that releasates from collagen- and thrombin-stimulated platelets inhibit neutrophil-induced vascular damage. Our results show that platelets protect tumors from vascular leakage induced by infiltrating leukocytes and that releasate from activated platelets has potent in vivo healing properties needed after leukocyte transmigration.

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Hendry, Shona, Roberto Salgado, Thomas Gevaert, Prudence A. Russell, Tom John, Bibhusal Thapa, Michael Christie, et al. "Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors." Advances In Anatomic Pathology 24, no. 6 (November 2017): 311–35. http://dx.doi.org/10.1097/pap.0000000000000161.

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Hendry, Shona, Roberto Salgado, Thomas Gevaert, Prudence A. Russell, Tom John, Bibhusal Thapa, Michael Christie, et al. "Assessing Tumor-infiltrating Lymphocytes in Solid Tumors." Advances In Anatomic Pathology 24, no. 5 (September 2017): 235–51. http://dx.doi.org/10.1097/pap.0000000000000162.

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Agarwala, Sandeep, DevendraKumar Yadav, Vishesh Jain, and AmitKumar Dinda. "Tumor-infiltrating lymphocytes in Wilms tumor." Indian Journal of Medical and Paediatric Oncology 41, no. 1 (2020): 34. http://dx.doi.org/10.4103/ijmpo.ijmpo_115_19.

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Karki, Shovana, and Sanjib Pariyar. "Tumor-infiltrating lymphocytes in colorectal carcinoma." Journal of Pathology of Nepal 11, no. 2 (September 30, 2021): 1859–63. http://dx.doi.org/10.3126/jpn.v11i2.38227.

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Background: Immunotherapy has become an important modality of treatment for CRC. The cells contributing to an effective immune response are CD8+ T cells of tumor-infiltrating lymphocytes. The present study aimed to assess the tumor-infiltrating lymphocytes on colorectal cancer and correlate them with other prognostic parameters. Material and methods: Cases of colectomy from April 2019 -Sept 2020 with a diagnosis of colorectal carcinoma were included in the study. Parameters i.e age, sex, size, location of the tumor, lymphovascular invasion, perineural invasion, T stage, N status, histological tumor type, and grade, resected margins were retrieved from the database of the department. The intensity of overall inflammatory cell reaction at the invasive tumor front was evaluated in H and E stained sections. Results: 56 cases of colorectal cancers were reported during the study period with M: F ratio of 1.15:1. The age ranged from 23-79years with a mean age of 54.3years. The tumors were predominant in the colon (50 cases) than the rectum. Colonic carcinomas had high-grade tumor-infiltrating lymphocytes as compared to rectal carcinomas. The grade of tumor-infiltrating lymphocytes was statistically significantly associated with T, N status, and grade of tumors. Conclusions: Inflammatory reactions at the invasive tumor front can be easily analyzed in resection specimens of colorectal cancers without additional costs. Low-grade tumor-infiltrating lymphocytes are indicative of high-stage tumors with a poor prognosis. Hence, the inclusion of tumor-infiltrating lymphocytes in pathological reports for risk stratification of the patient is mandatory.

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Rathinasamy, Anchana, Steffen Dettling, Yingzi Ge, Ludmila Umansky, Christel Herold-mende, Christoph Domschke, Florian Schütz, and Philipp Beckhove. "Emigration of tumor specific regulatory T cells from the bone marrow is triggered by S1P1 and correlates with their accumulation in breast tumors (TUM9P.1001)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 210.3. http://dx.doi.org/10.4049/jimmunol.194.supp.210.3.

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Abstract High regulatory T cell (Treg) infiltration in breast tumors is associated with reduced survival. However, the source of tumor infiltrating Treg and signals underlying their migration from lymphoid organs to the tumor tissue remain elusive. We here demonstrate that pronounced Treg infiltration in human breast tumors correlates with a selective reduction of tumor antigen specifc Treg from the bone marrow. Using MHC-II tumor peptide tetramers we furthermore show that tumor specific bone marrow Treg selectively express Sphingosine-1-phosphate receptor 1 (S1P1), the receptor that mediates cell egress. S1P1 was upregulated in Treg upon TCR stimulation mediated by bone marrow resident antigen presenting cells and triggered selective Treg but not conventional T cell migration in response to S1P gradients between bone marrow and blood which we found to be significantly increased in breast cancer patients. Taken together, our data suggests a crucial role for bone marrow antigen presenting cells in regulating the surface expression of S1P1 on tumor specific Treg in the bone marrow which may represent an important source of tumor infiltrating Treg.

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Haave, Hilde, Borghild Ljokjel, Helene Lybak, Svein E. Moe, Jan E. Berge, Olav K. Vintermyr, Lars Helgeland, and Hans J. Aarstad. "Tumor HPV Status, Level of Regulatory T Cells and Macrophage Infiltration Predict up to 20-Year Non-Disease-Specific Survival in Oropharynx Squamous Cell Carcinoma Patients." Biomedicines 10, no. 10 (October 5, 2022): 2484. http://dx.doi.org/10.3390/biomedicines10102484.

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Oropharynx squamous cell carcinoma (OPSCC) is of special interest because human papilloma virus (HPV) and/or smoking cause this disease. Influxes of inflammatory cells into such tumors are known to vary with prognoses. Aims: To study whether the density of tumor-infiltrating T lymphocytes and tumor-infiltrating macrophages predicted general 20-year overall survival (OS), as well as OS with only disease-specific survival (DSS) patients included. Methods: Biopsies from patients treated for OPSCC (n = 180) were stained by immunohistochemistry and the tumor cell macrophage (CD68), pan T lymphocytes (CD3), and regulatory T lymphocytes (Foxp3) densities were determined. The HE-determined percentage of matured tumor cells and the rate of invasion were calculated, and stromal desmoplasia were performed. Tumor HPV presence was studied by PCR. Twenty-year OS and five-year DSS patients were determined. Results: Tumor HPV status strongly predicted survival. High tumor infiltration of CD3, Foxp3 and CD68-positive cells predicted better twenty-year OS, with and without HPV stratification. Foxp3 and CD68 levels predicted OS, and 20-year among DSS patients, primarily among HPV(+) patients. Tumor HE-derived variables did not predict such survival. Conclusions: Tumor HPV status, level of Foxp3 tumor-infiltrating lymphocytes and CD68 tumor-infiltrating macrophages predicted up to 20-year OS of both all patients and disease-specific survived patients.

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Zakhartseva, Liubov, and Mariia Yanovytska. "TUMOR-INFILTRATING LYMPHOCYTES IN TRIPLE NEGATIVE BREAST CANCER: CORRELATIVE ANALYSES OF OWN DATA AND LITERATURE REVIEW." Ukrainian Scientific Medical Youth Journal, no. 2(110) (June 27, 2019): 31–41. http://dx.doi.org/10.32345/usmyj.2(110).2019.31-41.

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The article summarizes data and presents own study about the value of tumor-infiltrating lymphocytes as a prognostic factor for breast cancer including triple negative breast cancer lacking estrogen and progesterone receptors and HER2\new amplification. This tumor group is heterogeneous and has lower overall and disease-free survival rates; therapeutic options for this tumor group are limited compared to luminal and HER2-positive tumors. Triple negative breast tumors attract the attention of scientists as they require more individualized approach and additional prognostic factors in the treatment. The aim of this study is to conduct correlation analysis of tumor-infiltrating lymphocytes with survival rates, stage of disease and degree of differentiation of triple negative breast tumors. Also determination of the most "immunogenic" histological subgroups of triple negative breast cancer is done, as well as comparing of tumor-infiltrating lymphocytes measurement as a continuous number and divided into groups. Samples (n = 143) from patients with triple negative breast cancer undergoing treatment at the Kyiv City Clinical Oncology Center during 2010-2015 were used. The assessment of the number of tumor-infiltrating lymphocytes was performed on histological glasses retrospectively, following the recommendations of an international group for the determination of immune-oncological biomarkers. The number of tumor-infiltrating lymphocytes was evaluated as a continuous number and also divided into groups A (0-10%), B (10-40%) and C (40-90%). According to the results of the study, there was a high direct correlation between the continuous number of tumor-infiltrating lymphocytes and divided into groups (A, B, C). A weak direct correlation was found between tumor-infiltrating lymphocytes and tumor differentiation rates, a weak inverse correlation between tumor-infiltrating lymphocytes count and overall survival and stage of disease, in particular tumor size. The rate of tumor-infiltrating lymphocytes for all carcinomas with medullary characteristics was 100%, indicating a high "immunogenicity" of this histological subtype of tumors. The study confirms that tumor-infiltrating lymphocytes act as an additional prognostic marker for malignant breast tumors, in particular, triple negative breast cancer. Determination of tumor-infiltrating lymphocytes is advisable in the routine practice of the pathologist who investigates malignant breast tumors since it requires no additional reactions and is economically viable. It is advisable to use the recommendations of an international group of the determination of immuno-cancer biomarkers for the distribution of this indicator by groups A, B, C for convenience of description.

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Chae, Young Kwang, William Han Bae, Yeonjoo Choi, Young Suk Kim, Jonathan Forrest Anker, and Francis J. Giles. "The landscape of the tumor-infiltrating B cell and its association with T-cell and tumor microenvironment in human cancers." Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 76. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.76.

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76 Background: Compared to recent advances in our knowledge of T cell biology with success of immunotherapy, little progress has been made in understanding of the effects of B cells in tumor microenvironment and their interactions with T cells. Preclinical studies reported that B cells may have immune suppressive roles in tumor microenvironment via induction of T cell exhaustion. However, this association has not been shown in human tissues. We explored the landscape of tumor infiltrating B and T cells and their association with tumor microenvironment in various human cancers for which the FDA approved the use of immune checkpoint inhibitors. Methods: Expression patterns for 812 immune related genes from the TCGA database were utilized to define tumor infiltrating cells in 2951 patients with bladder urothelial carcinoma, renal clear cell carcinoma, skin cutaneous melanoma, lung squamous cell carcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma. Odds ratios (ORs) of the numbers of tumors with versus without activated B cell infiltration by the presence of activated CD8T cell infiltration were calculated. Results: Immune landscape of the six human cancers showed a consistent inverse association between tumor infiltrating activated B and CD8 T cells (OR = 0.18, p < 0.001). B cell infiltration was associated with increased expressions of immune checkpoints PD-L1, PD-1 and CTLA-4 and regulatory cytokines TGF-β, IL-10 and IL-35, which are known to be secreted by regulatory B cells. Angiogenic markers, such as angiopoietins, VEGF, MMP-9, CXCL10, CXCL11 and Tie2, showed differential expression patterns between B cell high and low groups. Conclusions: This is the first study that reports the inverse association between tumor infiltrating B and CD8 T cells in human tissues. The strong associations between B cell infiltration and increased expressions of suppressive cytokines and immune checkpoints suggest regulatory B cells may play a role in the T cell suppression in tumor microenvironment. Our results implicate that depleting B cells, leading to possible disinhibition of T cell activation, may be a future therapeutic option in potentiating T cell mediated immunity.

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Linnebacher, Michael, and Claudia Maletzki. "Tumor-infiltrating B cells." OncoImmunology 1, no. 7 (October 2012): 1186–88. http://dx.doi.org/10.4161/onci.20641.

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Labant, MaryAnn. "Infiltrating Solid Tumor Strongholds." Genetic Engineering & Biotechnology News 40, S1 (April 1, 2020): S4—S7. http://dx.doi.org/10.1089/gen.40.s1.02.

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Radvanyi, Laszlo G. "Tumor-Infiltrating Lymphocyte Therapy." Cancer Journal 21, no. 6 (2015): 450–64. http://dx.doi.org/10.1097/ppo.0000000000000162.

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Aranda, Juan M., Gary R. Cooper, Gregory Huff, and William H. Donnelly. "Infiltrating metastatic cardiac tumor." Clinical Cardiology 26, no. 5 (May 2003): 250. http://dx.doi.org/10.1002/clc.4960260511.

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Jin, Yin, Liping Tao, Shuqing Jin, and Weiyang Cai. "Patterns of immune infiltration in gastric cancer and their clinical significance." Japanese Journal of Clinical Oncology 51, no. 7 (April 23, 2021): 1067–79. http://dx.doi.org/10.1093/jjco/hyab054.

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Abstract Objective The malignant phenotypes of cancer are defined not only by its intrinsic tumor cells but also by the tumor-infiltrating immune cells activated and recruited to the cancer microenvironment. However, a comprehensive introduction of gastric cancer immune cell infiltration has not been identified so far. Methods In this study, we comprehensively analyzed the tumor-infiltrating immune cells abundance in gastric cancer for the first time by CIBERSORT. The meta-analysis, single-sample gene set enrichment analysis and hierarchical agglomerative clustering were used to measure and evaluate the respective proportions of 22 cell types of immune infiltration using normalized gene expression data. The fraction of tumor-infiltrating immune cells subpopulations was also evaluated to determine the associations with clinical features and molecular subtypes. Results Tumor-infiltrating immune cells are extensively involved in the pathogenesis and development of the gastric cancer. We discovered Tfh and activated CD4+ memory T cells were associated with poorer overall survival and Progression-free survival (PFS), but that naïve B cells were opposite for PFS. Unsupervised clustering analysis revealed there existed three tumor-infiltrating immune cells subgroups with distinct survival patterns. Specially, cluster 1 showed significantly better clinical outcome than other two clusters. Conclusions Collectively, our data explored the differences of tumor-infiltrating immune cells in gastric cancer, and these variations were likely to be important clues for prognosis and management of its future clinical implementation.

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Xu, Xiaowen, Jun Ma, Guanyu Yu, Qun Qiu, Wei Zhang, and Fuao Cao. "Effective Predictor of Colorectal Cancer Survival Based on Exclusive Expression Pattern Among Different Immune Cell Infiltration." Journal of Histochemistry & Cytochemistry 69, no. 4 (February 6, 2021): 271–86. http://dx.doi.org/10.1369/0022155421991938.

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Tumor-infiltrating immune/inflammatory cells, the important components of the tumor microenvironment (TME), remarkably affect the progression of human cancers. To understand the actual conditions within the TME of colorectal cancer (CRC), the interrelationship among tumor-infiltrating neutrophils, M2 macrophages, and regulatory T-cells (Tregs) was systematically analyzed. The infiltration conditions of CD66b+ neutrophils, CD163+ M2 macrophages, and FOXP3+ Tregs in tissue microarrays including 1021 cases of CRC were determined by immunohistochemical analysis. The prediction power of these immune cells for CRC prognosis was evaluated by subgroup analysis of the CRC cohort. Results revealed the existence pattern of infiltrating neutrophils, and Tregs/M2 macrophages fulfilled a “X-low implies Y-high” Boolean relationship, indicative of a mutually exclusive correlation between neutrophils and M2 macrophages, and between neutrophils and Tregs in the TME of CRC. What’s more, the tumor-infiltrating M2 macrophages and Tregs were associated with adverse prognostic factors, whereas neutrophils were corelated with favorable factors. The high infiltration of neutrophils predicted longer survival and better chemotherapeutic response. Nonetheless, high infiltration of M2 macrophages and Tregs predicted poor prognosis. The combination of these tumor-infiltrating immune cells can serve as an effective predictor for the survival of CRC and for the chemotherapeutic outcomes of stage II–III patients.

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Mukherjee, Geetashree, Swarnendu Bag, Prasenjit Chakraborty, Debdeep Dey, Samrat Roy, Prateek Jain, Paromita Roy, Richie Soong, Partha Pratim Majumder, and Suparna Dutt. "Density of CD3+ and CD8+ cells in gingivo-buccal oral squamous cell carcinoma is associated with lymph node metastases and survival." PLOS ONE 15, no. 11 (November 19, 2020): e0242058. http://dx.doi.org/10.1371/journal.pone.0242058.

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The tumor immune microenvironment is emerging as a critical player in predicting cancer prognosis and response to therapies. However, the prognostic value of tumor-infiltrating immune cells in Gingivo-Buccal Oral Squamous Cell Carcinoma (GBOSCC) and their association with tumor size or lymph node metastases status require further elucidation. To study the relationship of tumor-infiltrating immune cells with tumor size (T stage) and lymph node metastases (N stages), we analyzed the density of tumor-infiltrating immune cells in archived, whole tumor resections from 94 patients. We characterized these sections by immune-histochemistry using 12 markers and enumerated tumor-infiltrating immune cells at the invasive margins (IM) and centers of tumors (CT). We observed that a higher density of CD3+ cells in the IM and CT was associated with smaller tumor size (T1-T2 stage). Fewer CD3+ cells was associated with larger tumor size (T3-T4 stage). High infiltration of CD3+and CD8+ cells in IM and CT as well as high CD4+ cell infiltrates in the IM was significantly associated with the absence of lymph node metastases. High infiltrates of CD3+ and CD8+ cells in CT was associated with significantly improved survival. Our results illustrate that the densities and spatial distribution of CD3+ and CD8+ cell infiltrates in primary GBOSCC tumors is predictive of disease progression and survival. Based on our findings, we recommend incorporating immune cell quantification in the TNM classification and routine histopathology reporting of GBOSCC. Immune cell quantification in CT and IM may help predict the efficacy of future therapies.

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Sangam, Parinitha S., and Priyanka Parmesh. "Evaluation of tumour infiltrating lymphocytes in core needle biopsies and resected specimens of breast carcinoma." Journal of Pathology of Nepal 10, no. 2 (September 30, 2020): 1711–17. http://dx.doi.org/10.3126/jpn.v10i2.30227.

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Background: Tumour-infiltrating lymphocytes are important predictors of response to neoadjuvant therapy in breast cancer. It remains unclear whether Tumour infiltrating lymphocytes scores in core needle biopsies are closely representative of those in the whole tumour of surgically resected specimens. The study aims to evaluate the concordance between tumor-infiltrating lymphocytes scores of core needle biopsies and surgically resected specimens as per recommendations and to assess the reliability of tumor-infiltrating lymphocytes score in core needle biopsies. Materials and Methods: Retrospective study from January 2016 to March 2019 done in tertiary care hospital. Tumor-infiltrating lymphocytes scores were sub-classified as low (≤10%), intermediate (11–49%), and high (40-90%). Relevant statistical tests were used and reliability score was done by Fisher’s test. Results: The mean value of tumor-infiltrating lymphocytes in 34 cases was 27.03% in core needle biopsies and 34.6% in surgically resected specimens. High tumor-infiltrating lymphocytes score was seen in 8 (23.6%) and 11 (32.4%) cases and low to intermediate score was seen in 26 (76.4%) cases and 23 (67.6%) in core needle biopsies and surgically resected specimens respectively. Intermediate and high tumor-infiltrating lymphocytes categories in core needle biopsies accounted for good agreement with surgically resected specimens (60%-intermediate, 87.5 %-high). More than three cores had a better agreement. Conclusions: Tumor-infiltrating lymphocytes score in core needle biopsies is of reliable value in breast cancer. Discrepancies may occur in tumours with HER2neu phenotype, PR status, and younger age.

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Delfino, Teresita, Yingyun Wang, Soren Muller, Hina Iftikar, Zora Modrusan, Jill Schartner, and Sascha Rutz. "Foxp3+ regulatory T cells suppress T cell immunity in inflamed and non-inflamed tumors by distinct mechanisms." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 244.15. http://dx.doi.org/10.4049/jimmunol.204.supp.244.15.

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Abstract Foxp3+ regulatory T cells (Treg) are essential to prevent autoimmunity, but may also suppress anti-tumor immune responses. The relevance of Treg cell-mediated suppression in inflamed and non-inflamed (immune excluded or immune desert) tumors is not well understood. Here, we used Foxp3-DTR transgenic mice to selectively ablate Treg cells in mice with established tumors. We observed robust and rapid tumor clearance in a number of models, independent of the immune infiltration at baseline. These responses were driven by the induction of infiltration, proliferation, and cytokine production by CD8 T cells in tumor tissues. Importantly, pairing single cell TCR sequencing with transcriptome analysis revealed that CD8 T cells in the tumor acquired a progenitor exhausted phenotype and a clonally diverse TCR repertoire following Treg cell depletion. Pharmacological blockade of lymph node egress demonstrated that local Treg cell depletion and the resulting activation of tumor-infiltrating CD8 T cells was sufficient for tumor rejection in inflamed tumors. In contrast, short-term Treg cell depletion outside of the tumor and the resulting de novo generation of CD8 T cell responses facilitated the rejection of immune desert tumors. These data suggest that Treg cells play a critical role in suppressing both priming of novel anti-tumor CD8 T cell responses as well as limiting effector functionality of infiltrating CD8 T cells within the tumor microenvironment. More importantly, our data suggest that transient systemic Treg cell depletion can convert non-inflamed tumors into inflamed tumors.

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Song, Erwei, Shicheng Su, Jianyou Liao, Qiyi Zhao, Judy Lieberman, and Qiang Liu. "Naïve CD4+ T Cells, Recruited by CCL18 Secreted by Tumor-Associated Macrophages, Differentiate Within Breast Tumors into Tumor-Infiltrating Regulatory T Cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 155.6. http://dx.doi.org/10.4049/jimmunol.198.supp.155.6.

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Abstract The origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here we show that human breast tumor-infiltrating Tregs and naive CD4+ T cells have overlapping TCR repertoires, which barely overlap with circulating Treg sequences, suggesting that intratumoral Tregs develop from naive T cells in situ rather than from recruited Tregs. Naive CD4+ T cells, whose abundance in tumors is linked to poor prognosis, are recruited to human breast tumors when their PITPNM3 receptor recognizes the tumor-associated macrophage chemokine CCL18. In tumor-bearing humanized mice, blocking naive CD4+ T cell tumor recruitment by knocking down PITPNM3 reduces tumor-infiltrating Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in the tumor microenvironment. Inhibiting naïve CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy.

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Su, Shicheng, Jianyou Liao, Jiang Liu, Qiang Liu, and Erwei Song. "Conversion of CCL18-recruited naïve CD4+ T cells to tumor-infiltrating regulatory T cells in breast cancer and suppression of antitumor immunity." Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 114. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.114.

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114 Background: Tumor-infiltrating regulatory T cells (Tregs) play a central role in tumor immunosuppression. However, it remains unclear whether they are directly recruited from peripheral blood or converted from infiltrating naive T cells. Methods: We use full-length TCR ¦Á/¦Â repertoire to analyse the difference of T cell subsets from peripheral blood, primary tumors and draining lymph nodes in patents. Results: Infiltration of naive CD4+ T cells and Tregs are closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells in the tumors are recruited by tumor-associated macrophages (TAMs) via CCL18. In addition, naive T cells and memory T cells exhibit distinctive chemotactic response due to different expression of regulator of G-protein signaling 1(RGS1). Specific silencing CCL18 receptor-PITPNM3 in naive CD4+ T cells using CD4 aptamer-siRNA blocks their chemotaxis, and thus reduces infiltrating Tregs and inhibits tumor progression in humanized mice. By comparison, silencing RGS1 in memory CD8+ T cells using CD8 aptamer-siRNA enhance their recruitment to tumors and anti-tumor immune response in vivo. Conclusions: These findings provide mechanistic insights for Treg enrichment in breast cancer and suggest that modification of the CCL18-PITPNM3-RGS1 signaling pathway may be an attractive strategy for anticancer immunotherapy.

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Sacco, Alessandro, Anna Martina Battaglia, Cirino Botta, Ilenia Aversa, Serafina Mancuso, Francesco Costanzo, and Flavia Biamonte. "Iron Metabolism in the Tumor Microenvironment—Implications for Anti-Cancer Immune Response." Cells 10, no. 2 (February 2, 2021): 303. http://dx.doi.org/10.3390/cells10020303.

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New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert tumor-infiltrating immune cells to satisfy their iron demand, thus affecting the tumor immunosurveillance. In this review, we highlight how the bioavailability of this metal shapes complex metabolic pathways within the tumor microenvironment and how this affects both tumor-associated macrophages and tumor-infiltrating lymphocytes functions. Furthermore, we discuss the potentials as well as the current clinical controversies surrounding the use of iron metabolism as a target for new anticancer treatments in two opposed conditions: (i) the “hot” tumors, which are usually enriched in immune cells infiltration and are extremely rich in iron availability within the microenvironment, and (ii) the “cold” tumors, which are often very poor in immune cells, mainly due to immune exclusion.

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Huang, Bo, Zhang Lei, Gui-Mei Zhang, Dong Li, Chuanwang Song, Bo Li, Yanyan Liu, et al. "SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment." Blood 112, no. 4 (August 15, 2008): 1269–79. http://dx.doi.org/10.1182/blood-2008-03-147033.

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Abstract Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here, we report that tumor-infiltrating mast cells remodel tumor microenvironment and promote tumor growth. Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. Low concentrations of SCF efficiently induced the chemotactic migration of mast cells. Tumor-infiltrating mast cells, activated by higher concentrations of SCF, expressed multiple proinflammatory factors and increased IL-17 expression in tumors. The activity of NF-κB and AP-1 in tumor cells was intensified in the mast cell–remodeled inflammatory microenvironment. SCF-activated mast cells also exacerbated tumor immunosuppression by releasing adenosine and increasing T regulatory cells, which augmented the suppression of T cells and natural killer cells in tumors. These findings emphasize that the remodeling of the tumor microenvironment can actually be initiated by tumor cell–released SCF and suggest that mast cells are not only a participator but also a critical regulator of inflammation and immunosuppression in the tumor microenvironment.

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Pavlov, R. V., V. A. Aksionenko, and S. A. Selkov. "Cytokines production by mononuclear cells, infiltrating the epithelium tumour of ovaries." Journal of obstetrics and women's diseases 51, no. 1 (January 15, 2002): 74–77. http://dx.doi.org/10.17816/jowd90024.

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At auto serum presence one investigated IL1, IL2, IL4, IL6 and TNF6 production by mononuclear cells, infiltrating epithelium tumor of ovaries in 50 women of the patients by good-quality tumors, 30 patients by boundary tumors and 50 patients by an ovarian carcinoma. It was established, that IL1, TNF6 and IL6 production by mononuclear cells, infiltrating epithelium tumour of ovary, grew at malignancy of good-quality tumors and decreased the differentiation degree of cells of ovarian carcinoma. At malignancy of good-quality tumours and decreasing differentiation degree of cells of ovarian carcinoma the decrease of spontaneous and stimulated production of IL2 and stimulated production of IL4 by mononuclear cells, infiltrating epithelian tumour of ovary is revealed. The received data allow approving the increase of activity of mononuclear fagocytes, infiltrating epithelian tumor of ovarian during tumour progression, and also the decrease of T-cells activity in the 1-st and 2 types of immunity reactions in tumours of this localization. One of the possible reasons of cells immunity decrease at a tissue level in ovarian tumour can be increased production of cytokines by mononuclears, closing immunity reactions, in particular IL6.

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Stellas, Dimitris, Sevasti Karaliota, Vasiliki Stravokefalou, Breana Myers, Barbara K. Felber, and George N. Pavlakis. "Abstract 5603: Heterodimeric IL-15 (hetIL-15) immunotherapy reverses CD8+T cell metabolic dysfunction in murine breast tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5603. http://dx.doi.org/10.1158/1538-7445.am2022-5603.

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Abstract Introduction: Metabolic fitness and T cell survival are crucial in anti-tumor responses because nutrients are often scarce and other regulatory molecules may be unfavorable in the tumor microenvironment leading to T cell dysfunction, stress, and apoptosis. Tumor-infiltrating cytotoxic CD8+T cells often acquire an altered state of differentiation referred to as “exhaustion” and, as a result, they fail to control tumor outgrowth. IL-15 cytokine stimulates the generation, the proliferation and the cytotoxic function of tumor specific CD8+ T cells and NK cells. The objective of this study was to assess the effects of hetIL-15 immunotherapy after locoregional administration in triple negative breast cancer tumors (TNBC) and to evaluate the metabolic profile of the tumor infiltrating T cells. Study design and methods: We studied the therapeutic efficacy of hetIL-15 immunotherapy in murine EO771 orthotopic breast cancer model. We monitored the effect of the treatment on tumor size and immune infiltration using flow cytometry and immunohistochemistry. We also evaluated hetIL-15 effects on the cell metabolism and the mitochondrial function of the tumor-infiltrating immune cells, using flow cytometry, Seahorse flux analysis, Mitotracker, 2-NBDG and/or Bodipy staining. Results: hetIL-15 peritumoral administration, as monotherapy resulted in complete regression in 40% of the treated animals and increased survival. We demonstrated that tumor infiltrating cytotoxic CD8+T and NK cells were increased in hetIL-15 treated tumors and showed enhanced activation and proliferation, resulting in enhanced intratumoral immunological killing. Metabolic flux analysis of the tumor-infiltrating CD8+T cells from treated mice confirmed a rise in oxygen consumption rate (OCR) with substantial increase of spare respiratory capacity, which supports an activated/non exhausted phenotype of these hetIL-15 treated effector cells. Consistent with the above finding, tumor infiltrated CD8+T cells from hetIL-15 treated mice showed increased mitochondrial potential and fatty acid uptake, as evidenced by increased Mitotracker and Bodipy staining, respectively. In addition, tumor infiltrating CD8+T cells from hetIL-15 treated mice presented elevated extracellular acidification rate (ECAR) and showed a pronounced shift in the OCR to ECAR ratio in comparison to control, confirming their increased proliferating status. Conclusions: Our results indicate that hetIL-15 not only increases the infiltration and the cytotoxic properties of the CD8+T cells inside the tumors, but also enhances the metabolic reprogramming of T cells to achieve superior antitumor efficacy. We suggest that metabolic reprogramming of tumor-specific CD8+T cells might represent a strategy to promote survival in the metabolically hostile TME as part of an approach to enhance the clinical efficacy of immunotherapy. Citation Format: Dimitris Stellas, Sevasti Karaliota, Vasiliki Stravokefalou, Breana Myers, Barbara K. Felber, George N. Pavlakis. Heterodimeric IL-15 (hetIL-15) immunotherapy reverses CD8+T cell metabolic dysfunction in murine breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5603.

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Friedman, Kevin M., Peter A. Prieto, Laura E. Devillier, Colin A. Gross, James C. Yang, John R. Wunderlich, Steven A. Rosenberg, and Mark E. Dudley. "Tumor-specific CD4+ Melanoma Tumor-infiltrating Lymphocytes." Journal of Immunotherapy 35, no. 5 (June 2012): 400–408. http://dx.doi.org/10.1097/cji.0b013e31825898c5.

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Schneider, John, Florence M. Hofman, Michael L. J. Apuzzo, and David R. Hinton. "Cytokines and immunoregulatory molecules in malignant glial neoplasms." Journal of Neurosurgery 77, no. 2 (August 1992): 265–73. http://dx.doi.org/10.3171/jns.1992.77.2.0265.

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✓ Cytokines are important regulatory proteins controlling growth and differentiation of normal and malignant glial cells. Astrocytes and microglial cells produce and respond to many of the same cytokines employed by cells of the immune system. The authors have analyzed 15 histologically confirmed malignant glial neoplasms for the presence of infiltrating lymphocytes, macrophages, cytokines, and other immunoregulatory molecules using a panel of specific monoclonal and polyclonal antibodies on frozen-tissue sections. All neoplasms showed focal T-cell infiltration with CD8 cells predominating. Infiltration of activated macrophages (positive for CD11c, class II, and interleukin-2 receptor) was marked in all tumors. Within the neoplasm, tumor necrosis factor-α (TNF-α)- and interleukin (IL)-6-positive macrophages were prominent in five cases, while the tumor cells themselves were only weakly positive. In the other 10 cases, the numerous infiltrating macrophages were only rarely immunoreactive for TNF-α or IL-6. Transforming growth factor-β (TGF-β) immunoreactivity was most prominent in those tumors with little TNF-α-positive macrophage infiltration, although intratumoral variability was present. This study suggests that, in malignant gliomas, the cytokines TNF-α and IL-6, although weakly present in neoplastic cells, are most prominent in infiltrating macrophages and in those regions of the tumors that show little immunoreactivity for TGF-β. The important interactions among neoplastic, reactive glial, and inflammatory cells, which regulate tumor growth, are likely to be in part mediated through these molecules.

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Guirnalda, Patrick, Laurence Wood, Zhen-Kun Pan, Joel Crespo, and Yvonne Paterson. "IFNγ-inducible chemokines involved in lymphocyte trafficking and tumor regression are induced by immunotherapeutic Listeria monocytogenes (48.39)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 48.39. http://dx.doi.org/10.4049/jimmunol.186.supp.48.39.

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Abstract Using a transplantable HPV immortalized tumor model, TC.1, and a Listeria monocytogenes based immunotherapeutic that expresses HPV-E7, we have examined the requirements for T cell homing and infiltration following immunotherapy. Pro-inflammatory cytokines are produced in response to vaccination with Listeria based vaccines and underlie mechanisms of vaccine efficacy. Lymphocyte migration and infiltration into tumors and vaccine induced tumor regression are dependent upon a functional IFNγ receptor on the tumor cells. We hypothesized that vaccine induced and IFNγ dependent tumor regression relies on the presence of tumor derived, and IFNγ regulated chemokines. We noted the upregulation of CXCR3, CCR4 and CCR5 ligands at the mRNA and protein level in IFNγ and TNFα stimulated TC.1 tumor cells compared to unstimulated TC.1 cells. Vaccination with Listeria vaccines induced (i) the upregulation of tumor CCL4, CCL5 and CXCL9 and (ii) tumor infiltration of T cells bearing their cognate receptors. Tumor infiltrating lymphocytes consisted of both tumor antigen specific and Listeria antigen specific T cells. Chemokine receptor expression patterns varied among tumor infiltrating T cell subsets. IFNγ and TNFα stimulated CXCR3 ligand upregulation is a common feature among a variety of tumor cell lines and across a variety of tissues. Tumor cells are a source of effector T cell chemoattractants under vaccine induced pro-inflammatory conditions.

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Yamaki, T., T. Uede, N. Shijubo, and K. Kikuchi. "Functional analysis of mononuclear cells infiltrating into tumors. III. Soluble factors involved in the regulation of T lymphocyte infiltration into tumors." Journal of Immunology 140, no. 12 (June 15, 1988): 4388–96. http://dx.doi.org/10.4049/jimmunol.140.12.4388.

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Abstract We have analyzed the mechanisms controlling the accumulation of T lymphocytes in tumor tissues. Spleen cells, left or right popliteal lymph node cells, and tumor-infiltrating cells were obtained from tumor-inoculated rats and were cultured for 24 h. Culture supernatants were obtained and assessed for lymphocyte migration factor (LMF) activity with the use of a modified Boyden chamber. We found that tumor-infiltrating cells derived from T-9-sensitized rats produced LMF. Two waves of LMF production were observed. The first wave of LMF production was detected between 6 and 12 h (LMF-a) and the second wave of LMF production was detected between 4 and 6 days (LMF-4d and -6d) after tumor inoculation. The tumor-infiltrating cells consisted of heterogenous cell populations. We found that only tumor-infiltrating neutrophils of T-9-sensitized rats produced LMF-a. Five peaks of LMF (A through E) were detected upon fractionation of LMF-a using Mono Q anion exchange column chromatography. Peak D exhibited the strongest activity. The action of peak D was chemotactic, but not chemokinetic. The m.w. of peak D was 33,000 and 70,000. Only W3/25 (+) (helper/inducer) T cells were found to be sensitive to peak D. The production of LMF-a by purified tumor-infiltrating neutrophils in vitro is in agreement with the histologic observation that the infiltration of neutrophils precedes the appearance of W3/25 (+) T cells in tumor tissues of T-9-sensitized rats. It is thus likely that peak D of LMF-a is responsible for the infiltration of T lymphocytes into tumor tissues.

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Lin, Baisheng, Likun Du, Hongmei Li, Xiao Zhu, Liao Cui, and Xiaosong Li. "Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully." Biomedicine & Pharmacotherapy 132 (December 2020): 110873. http://dx.doi.org/10.1016/j.biopha.2020.110873.

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Poon, Grace FT, Frann Antignano, Lyz Boyd, Siobhan Ennis, Joe Deng, Andy I. Kokaji, Steven M. Woodside, Allen C. Eaves, and Sharon A. Louis. "Isolation of Tumor-Infiltrating Leukocytes from Mouse Tumors." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 242.2. http://dx.doi.org/10.4049/jimmunol.204.supp.242.2.

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Abstract Cell-based immunotherapy is being evaluated in various types of cancer and it is one of the most rapidly growing and promising areas of cancer research. Tumor-infiltrating leukocytes (TILs) consist of highly diverse leukocyte subsets with major roles in cancer immune surveillance. Due to their relatively low frequency, tumor heterogeneity, and the abundance of tissue debris in tumor samples, it is difficult to isolate or analyze TILs with sensitivity and precision. To address this challenge, we have developed a simple method for isolating CD45+ TILs from mouse tumors. Performance was evaluated in three commonly used mouse models, namely the B16 melanoma, CT26 colon carcinoma, and 4T1 mammary tumor models. Solid tumors were induced by subcutaneous implantation of B16, CT26.WT, and 4T1 cancer cell lines into syngeneic recipients. Starting with a single-cell suspension, TILs from tumor samples were labeled with an antibody complex that links CD45+ cells to magnetic particles, then separated using an EasySep™ magnet. Using this method, TILs were enriched from 17.5 +/− 5.8% to 90.1 +/− 6.0% (n = 13) from B16 tumors, 27.9 +/− 9.4% to 74.2 +/− 12.3 % (n = 9) from CT26 tumors, and 39.5 +/− 8.0% to 87.5 +/− 3.7% (n = 6) from 4T1 tumors. The protocol can be easily modified to achieve higher purity or recovery as required by adjusting the addition volume of the antibody complex or particles. Importantly, major immune subsets including T cells, B cells, and myeloid cells are recovered after isolation. The EasySep™ Mouse CD45 TIL Isolation Kit allows researchers to isolate leukocytes from tumors with ease, improving the TIL downstream workflow. Furthering our understanding of TILs will be essential for developing effective immunotherapeutic strategies.

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La Manna, Marco Pio, Diana Di Liberto, Marianna Lo Pizzo, Leila Mohammadnezhad, Mojtaba Shekarkar Azgomi, Vincenzo Salamone, Valeria Cancila, et al. "The Abundance of Tumor-Infiltrating CD8+ Tissue Resident Memory T Lymphocytes Correlates with Patient Survival in Glioblastoma." Biomedicines 10, no. 10 (October 1, 2022): 2454. http://dx.doi.org/10.3390/biomedicines10102454.

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Glial tumors alone account for 40% of all CNS tumors and present a low survival rate. The tumor microenvironment is a critical regulator of tumor progression and therapeutic effectiveness in glioma. Growing evidence from numerous studies of human solid tumor-infiltrating CD8+ T cells indicates that tissue-resident memory T cells (TRM) represent a substantial subpopulation of tumor-infiltrating lymphocytes (TILs). Although it is reported that some types of cancer patients with high immune infiltration tend to have better outcomes than patients with low immune infiltration, it seems this does not happen in gliomas. This study aimed to characterize TRMs cells in the glioma tumor microenvironment to identify their potential predictive and prognostic role and the possible therapeutic applications. Fluorescence activated cell sorting (FACS) analysis and immunofluorescence staining highlighted a statistically significant increase in CD8+ TRM cells (CD103+ and CD69+ CD8+ T cells) in gliomas compared to control samples (meningioma). In-silico analysis of a dataset of n = 153 stage IV glioma patients confirmed our data. Moreover, the gene expression analysis showed an increase in the expression of TRM-related genes in tumor tissues compared to normal tissues. This analysis also highlighted the positive correlation between genes associated with CD8+ TRM and TILs, indicating that CD8+ TRMs cells are present among the infiltrating T cells. Finally, high expression of Integrin subunit alpha E (ITGAE), the gene coding for the integrin CD103, and high CD8+ TILs abundance were associated with more prolonged survival, whereas high ITGAE expression but low CD8+ TILs abundance were associated with lower survival.

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Hu, Guoming, Shimin Wang, Feng Xu, Qiannan Ding, Wei Chen, Kefang Zhong, Liming Huang, and Qi Xu. "Tumor-Infiltrating Podoplanin+ Fibroblasts Predict Worse Outcome in Solid Tumors." Cellular Physiology and Biochemistry 51, no. 3 (2018): 1041–50. http://dx.doi.org/10.1159/000495484.

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Background/Aims: Tumor-infiltrating fibroblasts are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin+ fibroblasts in human solid tumors still remains controversial. Therefore, we performed the meta-analysis to better understand the role of this subpopulation in prognosis prediction for patients with solid tumor. Methods: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral podoplanin+ fibroblast density detected by immunohistochemical method and overall survival (OS) and/or disease-free survival (DFS) in patients with solid tumor, then computed extracted data into hazard ratios for OS, DFS and clinicopathological features with STATA 12.0. Results: A total of 4883 patients from 29 published studies were incorporated into this meta-analysis. We found that podoplanin+ fibroblast infiltration significantly decreased OS and DFS in all types of solid tumors. In stratified analyses, podoplanin+ fibroblast infiltration was significantly associated with worse OS in cholangiocarcinoma, breast, lung and pancreatic cancer. And these cells were inversely associated with DFS in breast, lung and pancreatic cancer. In addition, high density of these cells significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, TNM stage, lymphatic and vascular invasion of solid tumor. Conclusion: Podoplanin+ fibroblast infiltration leads to worse clinical outcome in solid tumors, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

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Stenina, Marina B., E. V. Tsareva, A. A. Zharov, and S. A. Tyulyandin. "Tumor infiltrating lymphocytes: biological essence and clinical significance in breast cancer." Russian Journal of Oncology 21, no. 1-2 (April 15, 2016): 92–100. http://dx.doi.org/10.18821/1028-9984-2015-21-1-92-100.

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In the review there are described the key stages of the development of anti-tumor immune response, as well there are presented the modern data on biological and clinical significance of tumor infiltrating lymphocytes in breast cancer; there is considered the method ofpathologic assessment of the pronouncement of lymphoid infiltration of the tumor; the results of clinical studies of prognostic and predictive role of immune markers including tumor infiltrating lymphocytes were analyzed.

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Xiong, Ying, Zewei Wang, Quan Zhou, Han Zeng, Hongyu Zhang, Zhaopei Liu, Qiuren Huang, et al. "Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients." Journal for ImmunoTherapy of Cancer 8, no. 1 (March 2020): e000447. http://dx.doi.org/10.1136/jitc-2019-000447.

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BackgroundIncreasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell infiltrations in clear cell renal cell carcinoma (ccRCC) and correlated the infiltration patterns with anti-tumor immunity and clinical outcomes.MethodsWe analyzed immune cell infiltrations in four independent cohorts, including the KIRC cohort of 533 patients, the Zhongshan ccRCC cohorts of 259 patients, the Zhongshan fresh tumor sample cohorts of 20 patients and the Zhongshan metastatic ccRCC cohorts of 87 patients. Intrinsic patterns of immune cell infiltrations were evaluated for associations with clinicopathological characteristics, underlying biological pathways, genetic changes, oncological outcomes and treatment responses.ResultsUnsupervised clustering of tumor infiltrating immune cells identified two microenvironment subtypes, TMEcluster-A and TMEcluster-B. Gene markers and biological pathways referring to immune evasion were upregulated in TMEcluster-B. TMEcluster-B associated with poor overall survival (p<0.001; HR 2.629) and recurrence free survival (p=0.012; HR 1.870) in ccRCC validation cohort. TMEcluster-B cases had worse treatment response (p=0.009), overall survival (p<0.001; HR 2.223) and progression free survival (p=0.015; HR 2.7762) in metastatic ccRCC cohort. The predictive accuracy of International Metastatic Database Consortium risk score was improved after incorporation of TME clusters.ConclusionsTMEcluster-A featured increased mast cells infiltration, prolonged survival and better treatment response. TMEcluster-B was a heavily infiltrated but immunosuppressed phenotype enriched for macrophages, CD4+T cells, Tregs, CD8+T cells and B cells. TMEcluster-B predicted dismal survival and worse treatment response in clear cell renal cell carcinoma patients.

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Shi, Guilan, Megan Scott, Cathryn G. Mangiamele, and Richard Heller. "Modification of the Tumor Microenvironment Enhances Anti-PD-1 Immunotherapy in Metastatic Melanoma." Pharmaceutics 14, no. 11 (November 10, 2022): 2429. http://dx.doi.org/10.3390/pharmaceutics14112429.

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Resistance to checkpoint-blockade treatments is a challenge in the clinic. Both primary and acquired resistance have become major obstacles, greatly limiting the long-lasting effects and wide application of blockade therapy. Many patients with metastatic melanoma eventually require further therapy. The absence of T-cell infiltration to the tumor site is a well-accepted contributor limiting immune checkpoint inhibitor efficacy. In this study, we combined intratumoral injection of plasmid IL-12 with electrotransfer and anti-PD-1 in metastatic B16F10 melanoma tumor model to increase tumor-infiltrating lymphocytes and improve therapeutic efficacy. We showed that effective anti-tumor responses required a subset of tumor-infiltrating CD8+ and CD4+ T cells. Additionally, the combination therapy induced higher MHC-I surface expression on tumor cells to hamper tumor cells escaping from immune recognition. Furthermore, we found that activating T cells by exposure to IL-12 resulted in tumors sensitized to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.

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Seifert, Lena, Ioana Plesca, Luise Müller, Ulrich Sommer, Max Heiduk, Janusz von Renesse, David Digomann, et al. "LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer." Cancers 13, no. 6 (March 15, 2021): 1297. http://dx.doi.org/10.3390/cancers13061297.

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T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8+ and Th1-polarized CD4+ T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3+ T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.

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Cardenas, Maria A., Nataliya Prokhnevska, Caroline S. Jansen, Viraj A. Master, and Haydn Kissick. "CD4 T cell phenotypes differentially modulate the CD8 T cell response in kidney cancer." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 165.1. http://dx.doi.org/10.4049/jimmunol.204.supp.165.1.

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Abstract CD8 T cell infiltration can independently predict survival and response to immunotherapy in kidney cancer patients. Given the importance of the CD8 T cell response in cancer, it is crucial to understand what signals promote their infiltration and support the maintenance of the anti-tumor response. The proportion of tumor infiltrating CD8 T cells, as measured by flow cytometry, was found to significantly correlate (R = 0.8, p<0.0001) with tumor infiltrating CD4 T cells in 160 renal cell carcinoma patients, suggesting that CD4 T cells may promote the tumor-specific CD8 T cell response. We hypothesize that the phenotype of tumor infiltrating CD4 T cells affects CD8 T cell differentiation and may contribute to the efficiency of the anti-tumor response. We performed flow cytometry analysis on a subset of kidney cancer patients to further characterize the CD4 populations in the tumor tissue. T-regulatory cells (Treg), defined by their master transcription factor FOXP3, accounted for 15.5 ± 7.2 % of the tumor infiltrating CD4 T cells. Importantly, the Treg population negatively correlated with CD8 differentiation and expression of effector-like molecules. Additionally, we found a Th1-like population expressing high levels of EOMES and GZMK that have previously been associated with cytolytic capacities. In conclusion, we found various subsets of CD4 T cells in the tumor that may differentially modulate CD8 T cell function and influence the anti-tumor response.

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Judge, Sean, Joshua Bloomstein, Sylvia Cruz, Aryana Razmara, Cyrus Sholevar, and Robert Canter. "646 Transcriptome analysis of tumor and matched infiltrating lymphocytes identifies potential new targets for augmenting intra-tumoral NK function in soft tissue sarcomas." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A675. http://dx.doi.org/10.1136/jitc-2021-sitc2021.646.

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BackgroundThe success of current immunotherapies in soft tissue sarcomas (STS) has been limited, although pre-clinical studies have shown evidence of natural killer (NK) cell activity. We set out to evaluate the gene expression profile of tumor-infiltrating NK cells, tumor-infiltrating T cells, and tumor-intrinsic genes with the goal of identifying potential novel therapeutic targets and potential drivers of immune infiltration.MethodsMatched peripheral blood and freshly excised STS tissue were collected and processed for FACS isolation of purified peripheral and tumor-infiltrating NK and T cells and tumor cells from STS patients undergoing surgery. Sorted CD45+CD3-CD56+ and CD45+CD3+CD56- immune populations and viable CD45- tumor cells were then evaluated by RNA sequencing analysis. To allow for analysis of survival differences and differential gene expression based on gene expression, we also queried the publicly available TCGA database to compare outcomes in high and low gene expression.ResultsComparing differential gene expression (DGE) of intra-tumoral NK cells to circulating NK cells revealed upregulation of genes involved in mitogen signaling inhibition (DUSP4) and metabolic function (SMPD3, SLC7A5) (P < 0.05), but not of genes associated with cytotoxic function (e.g. IFNG, GZMB). In contrast, intra-tumoral T cells showed significant upregulation of established activating (CD137) and inhibitory genes (TIM-3) compared to circulating T cells. Tumors with higher immune infiltration exhibited significantly increased expression of the pro-inflammatory receptor TLR4. TCGA analysis demonstrated that patients with high TLR4 expression had significantly improved survival compared to low expression (P = 0.03).ConclusionsUnlike T cells, which demonstrated significant DGE in activating and inhibiting receptors between circulating and tumor-infiltrating subsets, NK cells appear to have a more similar gene expression pattern between blood and tumor, with alterations in metabolic pathways. Tumor expression of TLR4 is associated with increased immune infiltration and warrants evaluation as a potential prognostic and predictive factor in STS.Ethics ApprovalThe collection of matched whole blood and tumor specimens was approved by the IRB at the University of California, Davis (Protocol # 218204-9).

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Soongsathitanon, Jarupa, Pranisa Jamjuntra, Nuttavut Sumransub, Supaporn Yangngam, Marjorie De la Fuente, Glauben Landskron, Peti Thuwajit, Marcela A. Hermoso, and Chanitra Thuwajit. "Crosstalk between Tumor-Infiltrating Immune Cells and Cancer-Associated Fibroblasts in Tumor Growth and Immunosuppression of Breast Cancer." Journal of Immunology Research 2021 (July 13, 2021): 1–15. http://dx.doi.org/10.1155/2021/8840066.

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Signals from the tumor microenvironment (TME) have a profound influence on the maintenance and progression of cancers. Chronic inflammation and the infiltration of immune cells in breast cancer (BC) have been strongly associated with early carcinogenic events and a switch to a more immunosuppressive response. Cancer-associated fibroblasts (CAFs) are the most abundant stromal component and can modulate tumor progression according to their secretomes. The immune cells including tumor-infiltrating lymphocytes (TILs) (cytotoxic T cells (CTLs), regulatory T cells (Tregs), and helper T cell (Th)), monocyte-infiltrating cells (MICs), myeloid-derived suppressor cells (MDSCs), mast cells (MCs), and natural killer cells (NKs) play an important part in the immunological balance, fluctuating TME between protumoral and antitumoral responses. In this review article, we have summarized the impact of these immunological players together with CAF secreted substances in driving BC progression. We explain the crosstalk of CAFs and tumor-infiltrating immune cells suppressing antitumor response in BC, proposing these cellular entities as predictive markers of poor prognosis. CAF-tumor-infiltrating immune cell interaction is suggested as an alternative therapeutic strategy to regulate the immunosuppressive microenvironment in BC.

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Ameer, Amna, Farhan Akhtar, Hafeez Ud Din, and Rabia Ahmed. "ASSESSMENT OF STROMAL AND INTRA-EPITHELIAL TUMOR INFILTRATING LYMPHOCYTES IN COLORECTAL CARCINOMA AT ARMED FORCES INSTITUTE OF PATHOLOGY." PAFMJ 71, no. 2 (April 28, 2021): 392–95. http://dx.doi.org/10.51253/pafmj.v71i2.4764.

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Objective: To conduct a morphological evaluation quantitatively of two types of tumor-infiltrating lymphocyte populations, including those located in the stroma and intraepithelial cancer structures, in patients with colorectal cancer. Study Design: Cross sectional study. Place and Duration of Study: Armed Forces Institute of Pathology, Rawalpindi, from Jan to Jul 2019. Methodology: Three levels of infiltration in the stroma by tumor infiltrating lymphocytes were determined. Level 1 was weak meaning (0-20% of stromal TILs), level 2 was moderate meaning (>20-50% of stromal TILs); and level 3 was strong meaning (50-90% of stromal TILs). TILs within tumor cells were divided into two groups. 0 meaning absent (no TILs present) and 1 meaning present (≥TILs in tumor cells) 1. Results: Out of 30 cases 22 were males and 8 females. Ages ranged between 25-83 with a mean of 57 years and a standard deviation of ± 16.4 years. All of the cases were diagnosed cases of adenocarcinoma. The levels of stromal tumor infiltrating lymphocytes was weak in 1 case, moderate in 18 cases and strong in 11 cases whereas intraepithelial lymphocytosis was seen in 22 cases. Conclusion: These results confirm that the infiltration of tumor infiltrating lymphocytes into the tumor in patients with colorectal carcinoma serves an important role in the invasion and progression of the disease, and should be considered in routine examinations.

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Gardian, Katarzyna, Sława Janczewska, and Marek Durlik. "Microenvironment Elements Involved in the Development of Pancreatic Cancer Tumor." Gastroenterology Research and Practice 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/585674.

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Introduction. In spite of intensive research during many years, pancreatic adenocarcinoma remains one of the deadliest cancers. The surgical intervention remains main possibility of treatment because chemotherapy and radiotherapy has a minimal impact on long-term survival. We are still looking for the weak points of this devastating disease.Materials and Methods. Pancreatic tumor tissue samples were collected from 36 patients. Immunohistochemistry staining was used to evaluate expression of growth factors and immune infiltrates. Activity of MMP2 and MMP9 was assessed by gelatin zymography on 7.5% SDS-PAGE gel with 0.1% gelatin.Results. All growth factors were strongly expressed in pancreatic tumor tissue. We found that level of expression of c-Met receptor was higher for G3 tumors than for G2 tumors. Also we found that active MMP2 was present at all stages of tumor while active MMP9 just at more advanced tumors. Abundant immune cells infiltration was distinctive for tumor tissue, especially macrophages were infiltrating tumor tissue. We found that amount of macrophages was associated with lymph nodes metastases.Conclusion. In our research we demonstrated that among many factors influencing tumor microenvironment c-Met receptor, infiltrating macrophages and MMP2 have significant influence on development and invasion of pancreatic cancer.

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HOLMES, E. CARMACK. "Immunology of Tumor Infiltrating Lymphocytes." Annals of Surgery 201, no. 2 (February 1985): 158–63. http://dx.doi.org/10.1097/00000658-198502000-00004.

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Lee, Sylvia, and Kim Margolin. "Tumor-Infiltrating Lymphocytes in Melanoma." Current Oncology Reports 14, no. 5 (August 10, 2012): 468–74. http://dx.doi.org/10.1007/s11912-012-0257-5.

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Journal articles on the topic 'Tumor Infiltrating'

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