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Journal articles on the topic 'Stress lymphoid surveillance'
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1
Enting, Deborah, Maria Luisa Iannitto, Fidelma Cahill, Aida Santaolalla, Simon Chowdhury, Mieke Van Hemelrijck, and Adrian C. Hayday. "Lymphoid stress-surveillance in prostate cancer." Journal of Clinical Oncology 33, no. 15_suppl (May 20, 2015): e22097-e22097. http://dx.doi.org/10.1200/jco.2015.33.15_suppl.e22097.
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Woolf, Richard, and Adrian Hayday. "Defining the lymphoid stress surveillance response in human skin." Lancet 383 (February 2014): S110. http://dx.doi.org/10.1016/s0140-6736(14)60373-1.
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Hayday, Adrian C. "γδ T Cells and the Lymphoid Stress-Surveillance Response." Immunity 31, no. 2 (August 2009): 184–96. http://dx.doi.org/10.1016/j.immuni.2009.08.006.
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Dart, Robin, Richard Woolf, Peter Irving, and Adrian Hayday. "Characterisation of the lymphoid stress surveillance response in human intestine." Lancet 387 (February 2016): S33. http://dx.doi.org/10.1016/s0140-6736(16)00420-7.
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Nussbaumer, Oliver, and Martin Thurnher. "Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance." Cells 9, no. 3 (March 22, 2020): 772. http://dx.doi.org/10.3390/cells9030772.
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Butyrophilin and butyrophilin-like proteins select γδ T cells and direct the migration of γδ T cell subsets to distinct anatomical sites. γδ T cells expressing Vδ2 paired with Vγ9 (Vγ9Vδ2 T cells) are the predominant γδ T cell type in human peripheral blood. Vγ9Vδ2 T cells, which cannot be studied easily in vivo because they do not exist in rodents, are often referred to as innate-like T cells. The genetically recombined γδ T cell receptor (TCR) that responds to isoprenoid-derived pyrophosphates (phosphoantigens) produced by infected and malignant cells in a butyrophilin-dependent manner qualifies them as therapeutically relevant components of the adaptive immune system. On the other hand, cell-surface proteins such as the C-type lectin CD161 mark a functional phenotype of Vγ9Vδ2 T cells that mediates TCR-independent innate-like responses. Moreover, CD56 (neural cell adhesion molecule, NCAM) and the G protein-coupled receptor GPR56 define Vγ9Vδ2 T cells with increased cytolytic potential and, like CD161, may also be expressed by dendritic cells, principally facilitating the generation of an innate-like immunological synapse. In this review, we summarise current knowledge of Vγ9Vδ2 T cell functional phenotypes that are critical to lymphoid stress surveillance.
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Shafi, S., P. Vantourout, G. Wallace, A. Antoun, R. Vaughan, M. Stanford, and A. Hayday. "An NKG2D-Mediated Human Lymphoid Stress Surveillance Response with High Interindividual Variation." Science Translational Medicine 3, no. 113 (November 30, 2011): 113ra124. http://dx.doi.org/10.1126/scitranslmed.3002922.
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Strid, J., O. Sobolev, B. Zafirova, B. Polic, and A. Hayday. "The Intraepithelial T Cell Response to NKG2D-Ligands Links Lymphoid Stress Surveillance to Atopy." Science 334, no. 6060 (December 1, 2011): 1293–97. http://dx.doi.org/10.1126/science.1211250.
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Johnson, Margarete D., Deborah A. Witherden, and Wendy L. Havran. "The Role of Tissue-resident γδ T Cells in Stress Surveillance and Tissue Maintenance." Cells 9, no. 3 (March 11, 2020): 686. http://dx.doi.org/10.3390/cells9030686.
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While forming a minor population in the blood and lymphoid compartments, γδ T cells are significantly enriched within barrier tissues. In addition to providing protection against infection, these tissue-resident γδ T cells play critical roles in tissue homeostasis and repair. γδ T cells in the epidermis and intestinal epithelium produce growth factors and cytokines that are important for the normal turnover and maintenance of surrounding epithelial cells and are additionally required for the efficient recognition of, and response to, tissue damage. A role for tissue-resident γδ T cells is emerging outside of the traditional barrier tissues as well, with recent research indicating that adipose tissue-resident γδ T cells are required for the normal maintenance and function of the adipose tissue compartment. Here we review the functions of tissue-resident γδ T cells in the epidermis, intestinal epithelium, and adipose tissue, and compare the mechanisms of their activation between these sites.
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Vulpis, Elisabetta, Alessandra Soriani, Cristina Cerboni, Angela Santoni, and Alessandra Zingoni. "Cancer Exosomes as Conveyors of Stress-Induced Molecules: New Players in the Modulation of NK Cell Response." International Journal of Molecular Sciences 20, no. 3 (January 31, 2019): 611. http://dx.doi.org/10.3390/ijms20030611.
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Natural killer (NK) cells are innate lymphoid cells that play a pivotal role in tumor surveillance. Exosomes are nanovesicles released into the extracellular environment via the endosomal vesicle pathway and represent an important mode of intercellular communication. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Moreover, the activation of the DNA damage response (DDR) and the induction of senescence represent two crucial modalities aimed at promoting the clearance of drug-treated tumor cells by NK cells. Emerging evidence has shown that stress stimuli provoke an increased release of exosome secretion. Remarkably, tumor-derived exosomes (Tex) produced in response to stress carry distinct type of DAMPs that activate innate immune cell populations. Moreover, stress-induced ligands for the activating receptor NKG2D are transported by this class of nanovesicles. Here, we will discuss how Tex interact with NK cells and provide insight into their potential role in response to chemotherapy-induced stress stimuli. The capability of some “danger signals” carried by exosomes that indirectly affect the NK cell activity in the tumor microenvironment will be also addressed.
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Monin, L., D. S. Ushakov, H. Arnesen, N. Bah, A. Jandke, M. Muñoz-Ruiz, J. Carvalho, et al. "γδ T cells compose a developmentally regulated intrauterine population and protect against vaginal candidiasis." Mucosal Immunology 13, no. 6 (May 29, 2020): 969–81. http://dx.doi.org/10.1038/s41385-020-0305-7.
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Abstract This most comprehensive analysis to date of γδ T cells in the murine uterus reveals them to compose a unique local T-cell compartment. Consistent with earlier reports, most cells expressed a canonical Vγ6Vδ1 TCR, and produced interleukin (IL)-17A upon stimulation. Nonetheless, contrasting with earlier reports, uterine γδ T cells were not obviously intraepithelial, being more akin to sub-epithelial Vγ6Vδ1+ T cells at several other anatomical sites. By contrast to other tissues however, the uterine compartment also included non-Vγ6+, IFN-γ-producing cells; was strikingly enriched in young mice; expressed genes hitherto associated with the uterus, including the progesterone receptor; and did not require microbes for development and/or maintenance. This notwithstanding, γδ T-cell deficiency severely impaired resistance to reproductive tract infection by Candida albicans, associated with decreased responses of IL-17-dependent neutrophils. These findings emphasise tissue-specific complexities of different mucosal γδ cell compartments, and their evident importance in lymphoid stress-surveillance against barrier infection.
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Vorontsova, Z. A., and E. F. Kudaeva. "Cellular reactions of the mucous membrane of the intestinal system after uranium incorporation." Morphological newsletter 28, no. 1 (July 28, 2020): 9–15. http://dx.doi.org/10.20340/mv-mn.2020.28(1):9-15.
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A pilot study, which was performed on white laboratory male rats and included a morphological study of the mucous membrane of the jejunum and colon, revealed the long-term effect of a single oral exposure to an aqueous solution of depleted uranium oxides; this supported dynamic changes in the studied criteria determining metabolic, regenerative, and local regulatory processes in one, three and six months. A lymphoid component appeared to be the criterion of high radio sensitivity and a marker of nonspecific protection indicating deterioration of homeostasis. In the time dynamics of long-term periods, a change in all the parameters was detected when using immunohistochemical, histochemical, and specific methods at the level of the epithelium lining the relief formations of the mucous membranes of the intestinal system organs. The oxidative stress resulting in three months after exposure to depleted uranium, which was evidenced by a significant decrease in the content of anti-apoptotic Bcl-2 protein in the epithelial cells of the jejunely mucosa. Signs of its delayed effect after six months in the colon induced the pronounced nature of the reactions of stromal cell components that determined patterns of protective mechanisms of the intestinal-associated immune system with a greater expressiveness in the jejunum. The factual material cited in the work suggests the existence of a homeostatic immune response in the mucous membrane of the small and large intestines that controls cell proliferation, as a special form of immune surveillance of the state of cytodifferentiation.
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Phillip, Jude M., Maria Nieves Calvo Vidal, Maria Victoria Revuelta, Nahuel Zamponi, Stephen Sloan, Benet Pera Gresely, Tharu Fernando, et al. "Heat Shock Factor 1 Reprograms the DLBCL Microenvironment to Evade Immune Surveillance and Support Tumor Growth." Blood 132, Supplement 1 (November 29, 2018): 2854. http://dx.doi.org/10.1182/blood-2018-99-117774.
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Abstract The primary components of the stromal lymphoma microenvironment (LME) are the cancer-associated fibroblasts (CAF) and the extracellular matrix (ECM) they produce. CAFs are derived from healthy fibroblasts that have been hijacked and transcriptionally reprogrammed by cancer cells into a novel biological entity to promote tumorigenesis. While the key effectors of these programs are largely unknown, recent data indicates that in a variety of solid tumors and T-acute lymphoblastic leukemias an important transcriptional programmer of the microenvironment is the Heat Shock Factor 1 (HSF1). Hence, we sought to determine the contribution of HSF1 within the stromal LME to the acquisition of lymphomagenic features in diffuse large B-cell lymphoma (DLBCL). We first analyzed the activity of HSF1 in 80 DLBCL patients by RNA-sequencing. Patients were segregated into having "high" and "low" HSF1 activity based on the expression of the canonical stress response target genes. We found distinct patterns of stromal-associated genes between DLBCL having "low" vs. "high" HSF1 activity. Furthermore, ChIP-sequencing data of lymphoma cells and CAFs showed the emergence of distinct transcriptional programs that are differentially orchestrated by HSF1. To delve deeper into the mechanism of these effects, we co-cultured lymphoma cells with fibroblasts having either HSF1 WT or HSF1 null in 3D collagen-containing lymphoma organoids. We found that only organoids harboring HSF1 WT fibroblasts were supportive of DLBCL cell proliferation. Moreover, DLBCL cells responsive and non-responsive to HSF1 downregulation in a cell-autonomous manner, failed to proliferate when cultured in HSF1-deficient LME organoids. To further elucidate this mechanism, we implanted a murine HSF1-positive DLBCL cell line (A20) into HSF1 WT (n=13) and HSF1 null (n=11) syngeneic mice and monitored lymphoma development for up to 14 days. We observed a continuous growth of HSF1-positive murine DLBCL in HSF1 WT mice; however, DLBCL in HSF1 null mice underwent spontaneous collapse after day 7, leading to almost complete tumor eradication. We further investigated the lymphoma microarchitecture, ECM biomechanics and composition in relation to the cellular components in serial tumor sections at several time points. At day 7, when no significant difference in tumor sizes exists between HSF1 WTs and nulls, we found significant differences in tissue stiffness (p=0.017), collagen microarchitectureby fiber alignment (p<0.001) and elastic fiber area (p<0.001). ECM proteomics by HPLC-MS/MS of the ECM-enriched fractions of these murine DLBCLs at days 5, 7 and 13 followed by network analysis demonstrated highly dynamic changes in ECM composition. Specifically, comparing the "matrisomes" of HSF1 WT and null tumors at day 7, we identified differentially regulated ECM modules that facilitate collagen functionalization and abundance of small leucine-rich proteoglycans; suggesting a failure of the HSF1 null stroma in efficiently remodeling the ECM. We identified dynamic changes in specific matrisome components with known roles in tumor proliferation and immune activity. These biochemical and biophysical changeswere in turn capable of modulating the cellular composition of DLBCL tumors. By day 7, the LME in HSF1 null was less supportive of lymphoma growth as measured by lower cellularity (p=4.5e-18) and proliferation of lymphoma cells by Ki67 (p=7.6e-6); and increased apoptosis by TUNEL (p=5.6e-5). In regards to CD31 positivity based on endothelial cells and vascularization, we observed no significant differences between HSF1 WT and HSF1 null tumors, however, there were significant changes in the repertoire of immune infiltrating cells. Specifically, HSF1 null LME harbored higher fractions of effector cd3+ T-cells (p=3.0e-6) and mac2+macrophages (p=9.4e-11); and a decrease in the suppressive cells cd3+foxp3+Tregs (p=6.6e-19) and cd11b+ gr1+myeloid-derived suppressor cells (p=0.0467). Taken together, our data in DLBCL specimens and cell lines, lymphoma-fibroblasts organoids, and a murine DLBCL model, all demonstrate that HSF1 activity in DLBCL drives an ECM program that confers microarchitectural and biophysical properties to the LME that are supportive of lymphoma cell proliferation and infiltration by immune suppressive populations. Disclosures Cerchietti: Celgene: Research Funding; Weill Cornell Medicine: Employment.
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Kyriakidis, Ioannis, Eleni Vasileiou, Claudia Rossig, Emmanuel Roilides, Andreas H. Groll, and Athanasios Tragiannidis. "Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies." Journal of Fungi 7, no. 3 (March 5, 2021): 186. http://dx.doi.org/10.3390/jof7030186.
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Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children with hematologic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and axicabtagene ciloleucel), CD20 (rituximab and biosimilars, 90Y-ibritumomab tiuxetan, ofatumumab, and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (brentuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (90Y-labelled BW 250/183), CD248 (ontuxizumab) and immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications.
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Satwani, Prakash, Aniket Saha, Sejal Bavishi, Frances Zhao, Janet Ayello, Carmella van de Ven, and Mitchell S. Cairo. "Romedepsin (RM), a Histone Deacytelase Inhibitor (HDACi), Significantly Increases the Expression of NKG2D Ligands, MIC A/B, In Pediatric Leukemia/Lymphoma Cells (LL), Resulting In Enhanced In Vitro and In Vivo NK Cytotoxicity In NOD-SCID Mice: Translational Approach for Adoptive NK Cell Targeted Immunotherapy." Blood 116, no. 21 (November 19, 2010): 4297. http://dx.doi.org/10.1182/blood.v116.21.4297.4297.
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Abstract Abstract 4297 Introduction: Natural killer (NK) cells recognize malignant cells through the tumor-associated expression of NKG2D ligands, including MIC A/B (Crewenka et al, Science, 1998). Tumor cells expressing ligands for NKG2D can become susceptible to NK cell killing despite normal MHC class I expression (Lanier LL, Nat Med, 2001). However, tumor cells may shed MIC A/B and escape immuno-surveillance. HDACi increases the expression of NKG2D ligands MIC A/B. Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase with numerous functions including regulation of cellular differentiation, stress and apoptosis, is also an important regulatory enzyme in the expression of MIC A/B in response to romidepsin (RM) (Skov et al, Cancer Res, 2005). Objective: To determine the expression of MIC A/B in response to RM in leukemia and lymphoma cells (LL), its influence on NK cell mediated in vitro and in vivo cytotoxicity in NOD-SCID mice and to investigate the role of the GSK-3 pathway in the regulation of expression of MIC A/B in response to RM. Methods: LL cells (106/ml, RS 4:11 [MLL-ALL], Ramos [Burkitt's lymphoma]) were exposed to RM (10 ng/mL) (generously provided by Gloucester Pharmaceuticals) for 24 hours, followed by FACS staining with PE-conjugated anti-MIC A/B. Peripheral blood NK cells were isolated via magnetic separation followed by 12 hrs incubation with interleukin-2 (IL-2) [3000 IU/ml]. Cytotoxicity assays (europium assay) were performed at effector target (E:T) ratio of 5–10:1. RS4:11 and Ramos cells were also pre-treated for 1 hour with 100mM lithium chloride (LiCl), a potent inhibitor of GSK-3 activity. The mammalian expression construct (ffLucZeo-pcDNA [generously provided by Laurence Cooper, MD, PhD]) was transfected to RS4:11 and Ramos cells using lipofectin. The transfected cells were selected by zeocin to make stable transfection cells using lipofectin. Six week old NOD-SCID mice received 5×106 LL cells subcutaneously. Once LL engraftment was established in NOD-SCID mice, the xenografted animals were divided in various groups, 1) Control NOD-SCID mice were injected with PBS, 2) NOD-SCID mice with leukemia or lymphoma, 3) NOD-SCID mice with leukemia or lymphoma + NK cell therapy and 4) NOD-SCID mice with leukemia or lymphoma + RM + NK cell therapy. NOD-SCID xenografted mice in group 3 received weekly injections of purified IL-2 activated adult NK cells (5×106) for 6 weeks and mice in group 4 received weekly injections of RM (4.4mg/kg) followed by an infusion of IL-2 activated NK cells 24 hrs later. Xenografted NOD-SCID mice were monitored by volumetric measurement of tumor size, bioluminescent imaging (Inoue et al, Exp. Hem, 2007) and survival. The survival distribution for each of the groups of mice was estimated using Kaplan-Meier estimates. The log-rank test was used to compare the survival distributions between treatment groups. Results: MIC A/B expression significantly increased in response to RM ([RS4:11 0.2% vs. 82%, p< 0.0001] and [Ramos 0.57% vs. 67%, p=0.0003]). Enhanced expression of MIC A/B in response to RM was inhibited when LL cells are pre-treated with LiCl RS 4:11 [RM vs RM+LiCl] 82% vs. 5%, p<0.0001; Ramos [RM vs. RM+LiCl] 67% vs. 35%, p<0.0001). In vitro cytotoxicity assays revealed significant increases against both RS 4:11 and Ramos cells at E:T ratio of 5–10:1 (p<0.01). The median survival time for NOD-SCID mice with RS4:11 was 24 days and RS4:11 + NK cell therapy was 34 days and RS4:11 +RM + NK cell therapy was: 46.5 days, respectively; Log-rank test p-value = 0.003. Median survival time for mice with Ramos was 16 days, Ramos + NK cells was 29 days and Ramos + RM + NK cell therapy was 32 days, respectively; Log-rank test p-value <0.001 Background: Expression of MIC A/B in LL cells is significantly increased by RM leading to enhanced susceptibility for NKG2D- MIC A/B mediated cytotoxicity by NK cells. NK cells + RM leads to increase in survival of NOD-SCID mice xenograft with LL. Furthermore, up-regulation of MIC A/B in LL cells secondary to RM exposure is in part regulated by the GSK-3 signal transduction pathway. Disclosures: No relevant conflicts of interest to declare.
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Olszewski, Adam J., Anna Dorota Chorzalska, Annette S. Kim, Peter J. Quesenberry, Mary L. Lopresti, Mary Anne Fenton, John L. Reagan, et al. "Recipients of Myelotoxic Chemotherapy Have Increased Prevalence of Clonal Hematopoiesis of Indeterminate Potential (CHIP) with a Typical Distribution of Chip-Associated Mutations." Blood 132, Supplement 1 (November 29, 2018): 3841. http://dx.doi.org/10.1182/blood-2018-99-111436.
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Abstract Background: Recent studies (Coombs et al., Cell Stem Cell 2017) have identified presence of clonal hematopoiesis of indeterminate potential (CHIP) in samples of solid tumors. CHIP is more prevalent among cancer survivors who subsequently develop therapy-related myeloid neoplasm (Gillis et al., Lancet Oncol 2017; Takahashi et al., Lancet Oncol 2017; Gibson et al., J Clin Oncol 2017). However, the relationship between CHIP and exposure to myelotoxic chemotherapy delivered as part of treatment for solid tumor is uncertain. We hypothesized that CHIP is more prevalent among recipients of myelotoxic chemotherapy compared with age-matched population. Methods: In this prospective, cross-sectional study, we collected peripheral blood samples from survivors of breast cancer or lymphoma who had received anthracycline- and/or alkylator-containing chemotherapy as part of their curative cancer therapy. All subjects had to be clinically free of cancer, and not have any hematologic disorders or unexplained cytopenias. We recruited patients age 50 to 70, because according to published population datasets (Jaiswal et al. and Genovese et al., NEJM 2014) in a cohort with mean age of 60 the expected CHIP prevalence would be about 5%. To minimize any potential contamination by circulating tumor cells, we isolated genomic DNA from purified CD45+ cells. We determined presence of CHIP by next-generation sequencing using an Illumina TruSeq Custom Amplicon kit (MiSeq V2.2). The assay targeted 757 coding exons of 96 genes commonly mutated in hematologic malignancies, including 20 CHIP-defining genes. To establish presence of CHIP, we required a known pathogenic variant with variant allele fraction (VAF) ≥ 2%. According to a pre-specified statistical plan, assuming one-sided alpha of 0.05, the study had 80% power to reject the null hypothesis of baseline CHIP prevalence of 5% in a cohort with sample size of 80. Results: Among 80 enrolled subjects, median age was 62 years (interquartile range, 56-67). There were 78% women, and 88% of subjects were white non-Hispanic. Patients had received doxorubicin- and/or cyclophosphamide-containing adjuvant or curative chemotherapy for breast cancer (56%) or lymphoma (44%). Median time from completion of chemotherapy to enrollment was 27 months (interquartile range, 11-59). We have completed sequencing of 72 samples (updated analysis will be provided at the meeting). Mean coverage depth was 1418x (±224), and ≥200x coverage was achieved in a mean 91.4% (±1.8%) of target amplicons. We detected CHIP in 12 subjects (17%; binomial 95% confidence interval: 10-27%; P=.0002 for the null hypothesis test of 5% prevalence). Mean VAF for the CHIP mutations was 5.3% (range, 1.4% to 29.9%), and patients had up to 4 CHIP-associated mutations (Fig. A). The CHIP-associated mutations had a typical distribution with most common mutations in DNMT3A, ASXL1, SRSF2, and TET2 (Fig. B). There was only 1 TP53 mutation, previously suggested to associate with exposure to chemotherapy (Coombs et al., 2017). Potentially germline variants of unknown significance (VUS) were found in 78% of patients, at mean VAF 49% (Fig. C), most commonly in ATM (12%), NOTCH2 (7%), BCORL1, and DNMT3B (6% each). Additionally, 2 patients had low-VAF variants suspicious for CHIP: ATM c.6059G>A (3.0%); PRPF8 c.790T>C (VAF 2.3%). Presence of CHIP was not significantly associated with age (within the narrow age range in the study cohort), sex, race, type of cancer (breast or lymphoma), count of white cells, red cells, platelets, or time elapsed from completion of chemotherapy. Conclusions: We have detected a significantly increased, more than 3 times the expected value, prevalence of CHIP among cancer survivors who had received myelotoxic chemotherapy. However, the distribution of mutations was typical for CHIP, without previously suggested over-representation of TP53. Further research is ongoing to determine whether presence of CHIP is related to a direct mutagenic effect of chemotherapy or competitive advantage of pre-existing CHIP clones after the hematopoietic stress of chemotherapy. Our data indicate that an affordable next-generation sequencing screen may be useful for detection of CHIP in cancer patients who are planning adjuvant chemotherapy, or as a surveillance tool after such therapy, to predict the risk of a therapy-related myeloid neoplasm and optimize personalized treatment strategies. Disclosures Olszewski: TG Therapeutics: Research Funding; Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Kim:Aushon Biosciences: Consultancy; LabCorp, Inc.: Consultancy; Papgene, Inc: Consultancy. Fenton:Astellas Pharma US: Other: Spouse employment. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding.
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Papanagnou, Eleni-Dimitra, Tina Bagratuni, Efstathios Kastritis, Issidora Papassideri, Evangelos Terpos, Meletios A. Dimopoulos, and Ioannis P. Trougakos. "Analysis of Molecular-Cellular Responses to Proteasome Inhibitors in Multiple Myeloma Patients; A Translational Approach of Proteasome Inhibitors In Vivo Effects from the Drosophila Experimental Model to Humans." Blood 126, no. 23 (December 3, 2015): 3250. http://dx.doi.org/10.1182/blood.v126.23.3250.3250.
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Abstract Organisms require efficient surveillance of proteome functionality to prevent disruption of proteostasis. Central to the proteostasis ensuring network is the proteasome, which degrades both normal short-lived ubiquitinated proteins and damaged or mutated proteins. Over-activation of the proteasome seems to represent a hallmark of advanced tumors and thus, its selective inhibition provides a strategy for the development of novel anti-tumor therapies. This approach is applied in multiple myeloma (MM) that represents the second most common hematological malignancy. Specifically, proteasome inhibitors have demonstrated clinical efficacy in the treatment of MM and mantle cell lymphoma and are evaluated for the treatment of other malignancies. Nevertheless, the impact of proteasome dysfunction in normal human tissues (which relates to side effects in the clinic) remains poorly understood. By using the fruit fly Drosophila melanogaster as an in vivo experimental platform to study proteasome physiology we found that proteasome functionality is sex-, tissue- and age-dependent. Oral administration of proteasome inhibitors (e.g. Bortezomib or Carfilzomib) in young flies suppressed proteasome activities in the somatic tissues; reduced motor function (recapitulating peripheral neuropathy of Bortezomib treatment in the clinic) and caused premature aging. It also increased oxidative stress and activated an Nrf2-dependent feedback regulatory circuit that upregulated proteasome genes in order to restore normal proteasome functionality. Moreover, in line with observations in the clinic, Carfilzomib was found to cause milder (as compared to Bortezomib) neuromusculatory toxicity and reduction of flies' lifespan. To address the question whether these findings can be translated in humans we started characterizing proteasome physiology in both healthy donors, as well as in MM patients treated with therapeutic proteasome inhibitors. For our studies we used isolated red blood cells (RBCs; represent an anucleate relatively "long-lived" proteome) and peripheral blood mononucleated cells (PBMCs; represent cell lineages with active genomic responses). Our analyses in healthy donors of different ages revealed significant variability of basal proteasome peptidase activities in both cell types. PBMCs expressed (as compared to RBCs) higher basal proteasome activities and RBCs from females had higher chymotrypsin-like activity as compared to RBCs from males of similar age. Furthermore, as in the flies' somatic tissues, proteasome activities were found (independently of sex and cell type) to decline during aging. Studies in RBCs and PBMCs isolated from MM patients treated with Bortezomib revealed donor-, cell type- and drug-specific readouts. In most (but not all) cases proteasome activities were suppressed in both cell types at 24-hrs post-drug administration. RBCs were particularly sensitive to the inhibitor and their proteasome activities remained low during the entire course of treatment. On the contrary, PBMCs were characterized by phases of rebound proteasome activities during the periods of no drug administration; these phases correlated with upregulation of proteasome genes expression, indicating that the feedback regulatory circuit which functions to restore proteasome activities in flies is also operational in humans. Additional gene expression analyses in PBMCs showed that proteasome inhibition also triggers the induction of genes involved in chaperon, autophagy, unfolded protein- and antioxidant-responses pathways; while, as in the fly model, the intensity of genes induction seems to decline during aging. Interestingly, in those patients who (despite treatment) showed no reduction of proteasome activities we found marginal gene expression alterations, suggesting that the observed gene induction largely depends on proteasome loss of function. Importantly, at the clinical level we observed a positive correlation between the degree of proteasome inhibition (in PBMCs or RBCS) and the depth of disease responses. The similarities between the Drosophila pharmacological model and the MM patients indicate that the molecular responses to proteasome malfunction are largely conserved in higher metazoans. We foresee that our ongoing studies will support a more personalized clinical therapeutic approach in hematological malignancies. Disclosures Terpos: Amgen: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Honoraria; Celgene: Honoraria, Other: Travel expenses. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria; Amgen: Honoraria.
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Raam, Liisi, Epp Kaleviste, Marina Šunina, Helen Vaher, Mario Saare, Ele Prans, Maire Pihlap, et al. "Lymphoid Stress Surveillance Response Contributes to Vitiligo Pathogenesis." Frontiers in Immunology 9 (November 20, 2018). http://dx.doi.org/10.3389/fimmu.2018.02707.
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Elisa, Binda, Manzo Antonio, Vitolo Barbara, Bugatti Serena, and Montecucco Carlomaurizio. "Exploiting NKG2D and lymphoid stress surveillance response in seronegative spondyloarthritis." Frontiers in Immunology 4 (2013). http://dx.doi.org/10.3389/conf.fimmu.2013.02.00712.
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"P092. Characterisation of the lymphoid stress surveillance response performed by human colon resident γδ T-cells." Journal of Crohn's and Colitis 10, suppl 1 (March 2016): S134.2—S135. http://dx.doi.org/10.1093/ecco-jcc/jjw019.211.
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Cheng, Yuan, Xiaobo Zhang, Zhiqi Wang, and Jianliu Wang. "Reconstruction of Immune Microenvironment and Signaling Pathways in Endometrioid Endometrial Adenocarcinoma During Formation of Lymphovascular Space Involvement and Lymph Node Metastasis." Frontiers in Oncology 10 (December 9, 2020). http://dx.doi.org/10.3389/fonc.2020.595082.
Full textAbstract:
BackgroundThe amplification or mutation of oncogenes and escape from immune surveillance systems promote tumor metastasis. However, subtle changes in the immune microenvironment and signaling pathways are poorly understood during the formation of lymphovascular space involvement (LVSI) and lymph node (LN) metastasis of endometrioid endometrial adenocarcinoma (EEA).Patients and methodsWe detected tumor immunology-related signaling pathways and immunocyte subtypes according to the mRNA levels of 750 oncogenes and genes relating to the tumor microenvironment and immune response using the Nanostring PanCancer IO 360 Panel in 24 paraffin-embedded tissues of EEAs and benign gynecological diseases. Internal reference genes were used for data normalization.ResultsAngiogenesis and immune cell adhesion signaling pathways were activated during LVSI formation of EEA progression. However, during the development of LVSI to LN metastasis, immune system signaling pathways were significantly inhibited, including antigen presentation, cytotoxicity, lymphoid compartment, interferon signaling, and costimulatory signaling pathways. Immune-related genes (CD69, HLA-DOA, ATF3, GBP1, AP2, DTX3L, EGR1, GBP4, TAP1, EIF2AK2, MX1, ISG15, STAT1, and HLA-DRA) were significantly downregulated in EEA with LN metastasis compared to those in EEA with LVSI. Instead, hypoxia, metabolic stress, epigenetic regulation, matrix remodeling, and metastasis signaling pathways were continuously activated in LN metastasis. We also found that neutrophils, macrophages, and mast cells might be involved in LVSI formation and LN metastasis in EEA.ConclusionsEEA with metastatic LNs showed significant immunosuppressive effects. Some oncogenes, matrix remodeling- and hypoxia-related genes, and neutrophil signatures showed higher expression, suggesting their potential as therapeutic targets and offering new immunotherapy strategies in EEA during LN metastasis.