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Dharma, Sanam, Sheila Figel, Tara Barone, Michael Ciesielski, and Robert Fenstermaker. "TAMI-63. GLIOBLASTOMA ASSOCIATED MESENCHYMAL STEM LIKE CELLS (G-MSC) WHICH INFILTRATE TUMORS IN HUMAN AND MOUSE ARE STRONGLY ASSOCIATED WITH IMMUNOSUPPRESSION." Neuro-Oncology 22, Supplement_2 (November 2020): ii227. http://dx.doi.org/10.1093/neuonc/noaa215.950.
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Abstract Glioblastoma (GBM) is the most aggressive form of brain cancer with an overall survival (OS) less than 16 months. Glioblastoma associated mesenchymal stem like cells (G-MSC) were identified in human patient samples, and higher presence of these cells in patient samples co-relates with lower overall survival. Our lab and others have also identified these cells in orthotopic GL261 glioblastoma murine models. We hypothesize that infiltration of G-MSC plays a key role in creating the highly immunosuppressive environment seen in GBMs. In order to investigate this, we utilized data from the TCGA database to stratify patients into two groups, showing higher or lower expression of the G-MSC markers (CD73, CD90, CD105). Patients expressing higher levels of G-MSC markers showed higher expression of CD4+ cells, as compared to patients with lower G-MSC marker expression. Further, patients with higher G-MSC markers showed high levels of PTGS2, the gene encoding cyclooxygenase 2 (COX2), a known tumor growth promoting and immunosuppressive molecule. We further investigated CD4+ T cell infiltration using GL261 orthotopic implants and observed that CD4+ T cells positively corelated with levels of G-MSC in these tumors. Our studies indicate that levels of G-MSC co-relate with immune cell infiltration and the expression of immunosuppressive factors such as COX2, underlining the importance of these cells in immunosuppression-driven resistance to therapy. These studies will be later utilized to develop rationale combination therapies to improve the overall survival in GBM.
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Syutkin, V. E., N. V. Borovkova, and M. S. Novruzbekov. "Biomarkers of tolerance and immunological monitoring in liver transplantation." Transplantologiya. The Russian Journal of Transplantation 12, no. 2 (June 18, 2020): 126–34. http://dx.doi.org/10.23873/2074-0506-2020-12-2-126-134.
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Introduction. We reviewed the literature data on clinical and laboratory parameters that allow predicting the development of operational tolerance in liver transplant recipients after their complete weaning from immunosuppressive therapy. The aim was to identify possible biomarkers of tolerance in liver transplant recipients with the successful complete weaning from immunosuppression for subsequent implementation in routine clinical practice. The cellular, humoral, and molecular markers of the liver transplant recipients who were completely withdrawn from immunosuppressive therapy without the development of graft dysfunction were estimated. The authors underlined the necessity of clinical trials for identifying biomarkers of the operational tolerance development.
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Kędzierska, Karolina, Krzysztof Sindrewicz, Katarzyna Sporniak-Tutak, Edyta Gołembiewska, Labib Zair, Jerzy Sieńko, Małgorzata Stańczyk-Dunaj, Irena Baranowska-Bosiacka, and Kazimierz Ciechanowski. "Does Immunosuppressive Therapy Affect Markers of Kidney Damage?" Annals of Transplantation 21 (March 3, 2016): 137–44. http://dx.doi.org/10.12659/aot.895275.
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Kovaleva, Olga V., Madina A. Rashidova, Daria V. Samoilova, Polina A. Podlesnaya, Valeria V. Mochalnikova, and Alexei Gratchev. "Immunosuppressive Phenotype of Esophagus Tumors Stroma." Analytical Cellular Pathology 2020 (August 20, 2020): 1–9. http://dx.doi.org/10.1155/2020/5424780.
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Background. Tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) contribute significantly to the development of immunosuppressive properties of a tumor. In this study, we performed immunohistochemical analysis of immune cells of esophageal tumors stroma. Methods. Paraffin-embedded tissue specimens from 48 esophageal squamous cell carcinoma (ESCC) patients were retrospectively collected for immunohistochemical analysis of stromal cells. For staining of macrophages, CD68, CD163, CD206, PU.1, and iNOS were used. For T cell detection, CD8, CD3, and FOXP3 were used. Also, we performed staining for PD-L1 that can be expressed on TAMs and tumor cells. Clinicopathological and survival data were collected and analyzed using the χ2 and Fisher exact tests, Kaplan–Meier curves, and the log-rank test. The correlation analysis was performed with Spearman’s rank correlation coefficient. Results. We found that FOXP3 expression was associated with age (p=0.042) and iNOS expression was associated with the disease stage (p=0.044). In addition, FOXP3 and CD163 appeared to be markers of good prognosis (HR=0.4420, p=0.0325, and HR=0.4447, p=0.0456, respectively). Significant association between PU.1+ and CD68+ macrophages (r=0.833; p≤0.001) and between PU.1+ and CD163+ macrophages (r=0.500; p≤0.001) was established; positive association between PU.1 and CD206 expression was also observed (r=0.250; p=0.043). Conclusions. Large amounts of CD163+ macrophages and FOXP3+ Т cells appear to be markers of good prognosis of ESCC. The number of PU.1+ macrophages strongly correlates with the number of CD68+ macrophages; therefore, usage of PU.1 as a potential macrophage marker can be recommended for esophageal tumors.
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Canzoni, Marco, Massimo Marignani, Maria Laura Sorgi, Paola Begini, Michela Ileen Biondo, Sara Caporuscio, Vincenzo Colonna, et al. "Prevalence of Hepatitis B Virus Markers in Patients with Autoimmune Inflammatory Rheumatic Diseases in Italy." Microorganisms 8, no. 11 (November 16, 2020): 1792. http://dx.doi.org/10.3390/microorganisms8111792.
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Chronic hepatitis B virus (HBV) infection may be reactivated by immunosuppressive drugs in patients with autoimmune inflammatory rheumatic diseases. This study evaluates HBV serum markers’ prevalence in rheumatic outpatients belonging to Spondyloarthritis, Chronic Arthritis and Connective Tissue Disease diagnostic groups in Italy. The study enrolled 302 subjects, sex ratio (M/F) 0.6, mean age ± standard deviation 57 ± 15 years, 167 (55%) of whom were candidates for immunosuppressive therapy. The Spondyloarthritis group included 146 subjects, Chronic Arthritis 75 and Connective Tissue Disease 83 (two patients had two rheumatic diseases; thus, the sum is 304 instead of 302). Ten subjects (3%) reported previous anti-HBV vaccination and tested positive for anti-HBs alone with a titer still protective (>10 IU/mL). Among the remaining 292 subjects, the prevalence of positivity for HBsAg, isolated anti-HBc, anti-HBc/anti-HBs, and any HBV marker was 2%, 4%, 18%, and 24%, respectively. A total of 26/302 (9%) patients with γ-globulin levels ≤0.7 g/dL were more frequently (p = 0.03455) prescribed immunosuppressive therapy, suggesting a more severe rheumatic disease. A not negligible percentage of rheumatic patients in Italy are at potential risk of HBV reactivation related to immunosuppressive therapy. Before starting treatment, subjects should be tested for HBV markers. Those resulting positive should receive treatment or prophylaxis with Nucleos (t) ides analogue (NUCs) at high barrier of resistance, or pre-emptive therapy, according to the pattern of positive markers. HB vaccination is recommended for those who were never exposed to the virus.
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Jablonska, Jadwiga, Malwina Rist, Ilona Spyra, Luisa Tengler, Maksim Domnich, Benjamin Kansy, Bernd Giebel, et al. "Evaluation of Immunoregulatory Biomarkers on Plasma Small Extracellular Vesicles for Disease Progression and Early Therapeutic Response in Head and Neck Cancer." Cells 11, no. 5 (March 5, 2022): 902. http://dx.doi.org/10.3390/cells11050902.
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Head and Neck Cancers (HNCs) have highly immunosuppressive properties. Small extracellular vesicles (sEVs), including exosomes, nanosized mediators of intercellular communication in the blood, carry immunosuppressive proteins and effectively inhibit anti-tumor immune responses in HNCs. This study evaluates immunosuppressive markers on sEVs from 40 HNC patients at different disease stages and 3- and 6-month follow-up after surgery and/or chemoradiotherapy. As controls, sEVs from normal donors (NDs) are examined. Immunoregulatory surface markers on sEVs were detected as relative fluorescence intensity (RFI) using on-bead flow cytometry, and their expression levels were monitored in the early and late stages of HNC and during follow-up. In parallel, the sEV-mediated apoptosis of CD8+ Jurkat cells was assessed. Together with TGF-β1 and PD-L1 abundance, total sEV proteins are elevated with disease progression. In contrast, total sEV protein, including TGF-β1, PD-1 and PD-L1, decrease upon therapy response during follow-up. Overall survival analysis implies that high sEV PD-1/PD-L1 content is an unfavorable prognostic marker in HNC. Consistently, the sEV-mediated induction of apoptosis in CD8+ T cells correlates with the disease activity and therapy response. These findings indicate that a combination of immunoregulatory marker profiles should be preferred over a single marker to monitor disease progression and therapy response in HNC.
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Na, Kwon Joong, and Hongyoon Choi. "Immune landscape of papillary thyroid cancer and immunotherapeutic implications." Endocrine-Related Cancer 25, no. 5 (May 2018): 523–31. http://dx.doi.org/10.1530/erc-17-0532.
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Although papillary thyroid cancer (PTC) is curable with excellent survival rate, patients with dedifferentiated PTC suffer the recurrence or death. As cancer immune escape plays a critical role in cancer progression, we aimed to investigate the relationship between differentiation and immune landscape of PTC and its implications for immunotherapy. Using The Cancer Genome Atlas data, we estimated the immune cell enrichment scores and overall immune infiltration, ImmuneScore, to characterize the immune landscape of PTC. Thyroid differentiation score (TDS) was calculated from 16 thyroid function genes. We demonstrated that ImmuneScore had a significant negative correlation with TDS, and BRAFV600E+ tumors showed significantly low TDS and high ImmuneScore. Enrichment scores of myeloid cells and B-cells were negatively correlated with TDS, while those of plasma cells were positively correlated with TDS. In addition, the association between TDS, ImmuneScore and immunosuppressive markers (CTLA-4, PD-L1, HLA-G) were evaluated according to BRAFV600E status. All immunosuppressive markers expression had a significant negative correlation with TDS, and they were significantly higher in BRAFV600E+ status. Subgroups were divided by median values of TDS and ImmuneScore, and immunosuppressive markers of these subgroups were compared. The immunosuppressive markers expression was the highest in high ImmuneScore and low TDS subgroup. Furthermore, ImmuneScore had a significant association with recurrence-free survival, irrespective of clinicopathologic factors including BRAFV600E status. These findings based on gene expression data illuminate the immune landscape of PTC and its association with TDS, immunosuppressive markers and recurrence. Our results would be extended to investigate immunotherapeutic approaches in PTC.
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Vanhaver, Christophe, Pierre van der Bruggen, and Annika M. Bruger. "MDSC in Mice and Men: Mechanisms of Immunosuppression in Cancer." Journal of Clinical Medicine 10, no. 13 (June 28, 2021): 2872. http://dx.doi.org/10.3390/jcm10132872.
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Myeloid-derived suppressor cells (MDSCs) expand during pathological conditions in both humans and mice and their presence is linked to poor clinical outcomes for cancer patients. Studying MDSC immunosuppression is restricted by MDSCs’ rarity, short lifespan, heterogeneity, poor viability after freezing and the lack of MDSC-specific markers. In this review, we will compare identification and isolation strategies for human and murine MDSCs. We will also assess what direct and indirect immunosuppressive mechanisms have been attributed to MDSCs. While some immunosuppressive mechanisms are well-documented in mice, e.g., generation of ROS, direct evidence is still lacking in humans. In future, bulk or single-cell genomics could elucidate which phenotypic and functional phenotypes MDSCs adopt in particular microenvironments and help to identify potential targets for therapy.
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Koldarova, Evelina, Bahrambek Mukhamedov, and Aziz Aliev. "A clinical case of an immunosuppressive generalized form of Kaposi's sarcoma in a patient with pemphigus vulgaris." Journal of Clinical Medicine of Kazakhstan 19, no. 6 (December 30, 2022): 100–103. http://dx.doi.org/10.23950/jcmk/12695.
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The article presents the literature data on Kaposi's sarcoma a lymphangioproliferative neoplasia induced by the Herpes Virus type 8. The main forms, clinical manifestations and treatment are described. A clinical case of the development of an immunosuppressive generalized form of Kaposi's sarcoma induced by glucocorticosteroid therapy in a patient with pemphigus vulgaris is presented. With this clinical example, it is important to emphasize the potential risk of Kaposi's sarcoma on the background of secondary immunosuppression. Immunosuppressive Kaposi's sarcoma (iatrogenic type) is most often associated with long-term use of immunosuppressive therapy in transplantation organs and in patients receiving immunosuppressive therapy for autoimmune diseases, which leads to an increased risk of developing Kaposi's sarcoma by 150-1000 times compared with the general population. The ratio of men and women with this type is 2:1, while with the idiopathic (classical) - 17:1. Reliable diagnosis of the disease is necessary, based on a combination of history data, clinical and histological patterns of the pathological process, as well as additional laboratory markers, which will allow timely determination of further patient management tactics and, accordingly, provide a more favorable prognosis for the course of the disease.
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Kuebler, H. R., J. Dannull, T. Y. Tseng, A. Zhang, Z. Su, P. Dahm, and J. Vieweg. "Immature myeloid cell (ImC)- mediated immunosuppression in advanced renal cell cancer (RCC)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10042. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10042.
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10042 Background: RCC affects the immunsystem by inhibiting the process of differentiation of antigen-resenting cells from their myeloid precursors by secreting tumor-derived factors such as VEGF. ImC induce a profound state of immune suppression that foster tumor tolerance by inhibition of tumor specific T cells. In this study, we asked whether increased ImC frequencies can be found in peripheral blood from RCC patients and if ImC frequencies correlated positively with increased levels of tumor-derived serum markers. Methods: ImC frequencies from healthy volunteers and RCC patients were determined by FACS. ImC were isolated by magnetic bead separation techniques and their immunosuppressive activity was determined in IFN-γ ELISPOT analyses, CTL and T-cell proliferation assays. The production of reactive oxygen species by ImC was analyzed utilizing specific probes and inhibitors. Tumor-derived serum markers were quantified by ELISA, enzyme immune assays and cytometric bead arrays. Microarray analyses were performed to identify novel, highly specific ImC markers. Results: RCC patients demonstrate higher ImC frequencies (0.8 - 3.2% of total PBMC) compared to healthy donors. The increased ImC frequencies are positively correlated with serum levels of VEGF, PGE-2, IL-13 and M-CSF in RCC patients and the concentration of byproducts of oxidative burst, including iso-prostane and malondialdehyde, was significantly enhanced. Isolated ImC exhibited profound immunosuppressive effects on CTL and CD4+ T cell response in an antigen specific fashion. Immunosuppression by ImC was mediated by release of ROS, including peroxide and superoxide anions and by generation of nitric oxide radicals as evidenced in functional assays. Results from microarray analyses reveal EP-1, EphA5, and PEX-5 as novel ImC markers. Conclusions: These data suggest that RCC may induce the development of immunosuppressive ImC population through secretion of cytokines such as VEGF, IL-13, M-CSF and PGE-2. Inhibition of specific cytokine activity or the use of differentiating agents may represent strategies to decrease immunosuppressive ImC population. Results from a phase I clinical trial investigating the effects of all-trans retinoic acid (ATRA) on differentiation of ImC in RCC patients will be presented. No significant financial relationships to disclose.
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Guillaume, Zoé, Marie Auvray, Yann Vano, Stéphane Oudard, Dominique Helley, and Laetitia Mauge. "Renal Carcinoma and Angiogenesis: Therapeutic Target and Biomarkers of Response in Current Therapies." Cancers 14, no. 24 (December 14, 2022): 6167. http://dx.doi.org/10.3390/cancers14246167.
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Due to the aberrant hypervascularization and the high immune infiltration of renal tumours, current therapeutic regimens of renal cell carcinoma (RCC) target angiogenic or immunosuppressive pathways or both. Tumour angiogenesis plays an essential role in tumour growth and immunosuppression. Indeed, the aberrant vasculature promotes hypoxia and can also exert immunosuppressive functions. In addition, pro-angiogenic factors, including VEGF-A, have an immunosuppressive action on immune cells. Despite the progress of treatments in RCC, there are still non responders or acquired resistance. Currently, no biomarkers are used in clinical practice to guide the choice between the different available treatments. Considering the role of angiogenesis in RCC, angiogenesis-related markers are interesting candidates. They have been studied in the response to antiangiogenic drugs (AA) and show interest in predicting the response. They have been less studied in immunotherapy alone or combined with AA. In this review, we will discuss the role of angiogenesis in tumour growth and immune escape and the place of angiogenesis-targeted biomarkers to predict response to current therapies in RCC.
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Dummer, Reinhard, Kelly Biette, Daniel Gusenleitner, Radha Ramesh, Celeste Lebbe, Victoria Atkinson, Mario Mandalà, et al. "Effect of first-line spartalizumab + dabrafenib + trametinib on immunosuppressive features detected in peripheral blood and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 10034. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.10034.
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10034 Background: Spartalizumab + dabrafenib + trametinib has previously shown a high response rate of 78% (28 of 36 pts), with a complete response (CR) rate of 42%. A correlative analysis of gene expression signatures (GES)/pathways using whole-transcriptome RNA-seq data from tissue showed that pts with a CR had significantly lower expression levels of immunosuppressive factors in the tumor microenvironment (TME) at baseline (BL). Here we analyze BL peripheral blood markers in the same cohort of pts to assess whether liquid markers can also predict response and clinical outcome to spartalizumab + dabrafenib + trametinib. Methods: The Phase III COMBI-i study (NCT02967692) is evaluating spartalizumab + dabrafenib + trametinib in pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma. In parts 1 (safety run-in; n = 9) and 2 (biomarker cohort; n = 27), blood and tissue samples were collected at BL, on treatment after 2-3 wk and 8-12 wk, and at disease progression. Lactate dehydrogenase (LDH) and other blood-based markers (including cytokine profiling [n = 45] and blood RNA-seq [114 signatures]) were assessed in all 36 pts. Pts were divided into 2 groups of 24 and 12 pts based on progression-free survival (PFS) of > 1 or < 1 y. Results: In addition to LDH, previously described blood markers such as neutrophil to lymphocyte ratio (NLR) and plasma IL-8 were identified among other neutrophil and immunosuppressive features as top candidates associated with PFS > 1 y. Low plasma IL-8 levels were also associated with CR, and multivariate models suggested that IL-8 may add independent predictive value to LDH and NLR for PFS > 1 y and CR. Pts with high IL-8 levels in the circulation were characterized by high neutrophil chemokine signaling (ρ = 0.553) and high neutrophil markers (ρ = 0.466) in the tumor as measured by RNA-seq GES levels. We observed a decrease in plasma IL-8 levels from BL upon treatment with spartalizumab + dabrafenib + trametinib. Conclusions: Our peripheral blood marker analysis confirmed recent findings from tissue samples that intratumoral immunosuppressive features may preclude a CR and are associated with poor outcomes. High BL plasma IL-8 levels may be associated with an immunosuppressive TME. Further validation is warranted; the randomized placebo-controlled part 3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
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Li, Ruixue, Renyong Wang, Shijie Zhong, Farhan Asghar, Tiehan Li, Lei Zhu, and Hong Zhu. "TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ." Open Life Sciences 16, no. 1 (January 1, 2021): 1193–202. http://dx.doi.org/10.1515/biol-2021-0118.
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Abstract Transforming growth factor (TGF)-β1 and mesenchymal stromal cells (MSCs) are two effective immunosuppressive agents for organ transplantation technology. This study aims to explore the molecular mechanism of TGF-β1-overexpressed MSCs on T cell immunosuppression. To achieve that, BM-MSCs were isolated from canine bone marrow, and their osteogenic differentiation and surface markers were detected. The TGF-β1 gene was transferred into lentivirus and modified MSCs (TGF-β1/MSCs) by lentivirus transfection. Furthermore, TGF-β1/MSCs were co-cultured with T cells to investigate their effect on differentiation and immune regulation. Results showed that TGF-β1/MSCs significantly downregulated the proportion of CD4+ CD8+ T cells in lymphocytes and significantly upregulated the proportion of CD4+ CD25+ T cells. Moreover, TGF-β1/MSCs significantly upregulated the expression of IL-10 in CD4+ T cells and downregulated the expression of IL-17A, IL-21, and IL-22. Meanwhile, interferon-γ (IFN-γ) neutralizing antibody blocked the effects of TGF-β1/MSCs on the differentiation inhibition of Th17. Overall, our results confirm the strong immunosuppressive effect of TGF-β1/MSCs in vitro and demonstrate that IFN-γ mediates the immunosuppressive effect of TGF-β1/MSC.
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Draxler, Dominik F., Kah Yep, Gryselda Hanafi, Anoushka Winton, Maria Daglas, Heidi Ho, Maithili Sashindranath, et al. "Tranexamic acid modulates the immune response and reduces postsurgical infection rates." Blood Advances 3, no. 10 (May 24, 2019): 1598–609. http://dx.doi.org/10.1182/bloodadvances.2019000092.
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Abstract Tranexamic acid (TXA) is an antifibrinolytic agent that blocks plasmin formation. Because plasmin is known to promote inflammatory and immunosuppressive responses, we explored the possibility that plasmin-mediated immunosuppression in patients undergoing cardiac surgery can be directly reversed by TXA and decrease postoperative infection rates. The modulatory effect of TXA on inflammatory cytokine levels and on innate immune cell activation were evaluated with multiplex enzyme-linked immunosorbent assay and flow cytometry, respectively. Postoperative infection rates were determined in patients undergoing cardiac surgery and randomized to TXA (ACTRN12605000557639; http://www.anzca.edu.au). We demonstrate that TXA-mediated plasmin blockade modulates the immune system and reduces surgery-induced immunosuppression in patients following cardiac surgery. TXA enhanced the expression of immune-activating markers while reducing the expression of immunosuppressive markers on multiple myeloid and lymphoid cell populations in peripheral blood. TXA administration significantly reduced postoperative infection rates, despite the fact that patients were being administered prophylactic antibiotics. This effect was independent of the effect of TXA at reducing blood loss. TXA was also shown to exert an immune-modulatory effect in healthy volunteers, further supporting the fibrin-independent effect of TXA on immune function and indicating that baseline plasmin levels contribute to the regulation of the immune system in the absence of any comorbidity or surgical trauma. Finally, the capacity of TXA to reduce infection rates, modulate the innate immune cell profile, and generate an antifibrinolytic effect overall was markedly reduced in patients with diabetes, demonstrating for the first time that the diabetic condition renders patients partially refractory to TXA.
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Oshida, Keiyu, Akihisa Maeda, Mika Kitsukawa, Sachiko Suga, Shunsuke Iwano, Tomoya Miyoshi, and Yohei Miyamoto. "Novel gene markers of immunosuppressive chemicals in mouse lymph node assay." Toxicology Letters 205, no. 1 (August 2011): 79–85. http://dx.doi.org/10.1016/j.toxlet.2011.05.1017.
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Manuszak, Claire, Martha Brainard, Emily Thrash, F. Stephen Hodi, and Mariano Severgnini. "Standardized 11-color flow cytometry panel for the functional phenotyping of human T regulatory cells." Journal of Biological Methods 7, no. 2 (April 13, 2020): e131. http://dx.doi.org/10.14440/jbm.2020.325.
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T regulatory cells (Tregs) are a cell subset that can suppress immune responses to maintain homeostasis and self-tolerance. In some scenarios, the immunosuppressive nature could be associated to other pathological developments such as autoimmune diseases and cancers. Due to the importance of Tregs in disease pathogenesis, we developed and validated an 11-color flow cytometry panel for phenotypic and functional detection of Treg markers using healthy human donor peripheral blood mononuclear cells (PBMCs). Our panel contains 4 Treg surface proteins and 2 functional cytokines as well as T-lymphocyte lineage markers CD3, CD4, and CD8. Our data shows an increase in expression of markers CD25, FoxP3, CTLA4, GITR and intracellular cytokines IL4 and TGFβ when comparing unstimulated samples to CD3/CD28 bead stimulated samples. This 11-color panel can be used to functionally evaluate immunosuppressive Tregs in human PBMC samples.
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Kuol, Nyanbol, Majid Davidson, Jimsheena Karakkat, Rhiannon T. Filippone, Margaret Veale, Rodney Luwor, Sarah Fraser, Vasso Apostolopoulos, and Kulmira Nurgali. "Blocking Muscarinic Receptor 3 Attenuates Tumor Growth and Decreases Immunosuppressive and Cholinergic Markers in an Orthotopic Mouse Model of Colorectal Cancer." International Journal of Molecular Sciences 24, no. 1 (December 29, 2022): 596. http://dx.doi.org/10.3390/ijms24010596.
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Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host’s immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study’s results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host’s immunity.
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Svicher, Valentina, Romina Salpini, Vincenzo Malagnino, Lorenzo Piermatteo, Mohammad Alkhatib, Carlotta Cerva, and Loredana Sarmati. "New Markers in Monitoring the Reactivation of Hepatitis B Virus Infection in Immunocompromised Hosts." Viruses 11, no. 9 (August 25, 2019): 783. http://dx.doi.org/10.3390/v11090783.
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Hepatitis B virus (HBV) persistence is at the basis of HBV reactivation as a consequence of chemotherapy and immunosuppressive treatments. The identification of early viral replication indicators and markers of effective HBV immunological control would be useful in monitoring patients who are at risk of potential viral reactivation during the course of immunosuppressive treatment. Currently, international guidelines have shared some criteria to identify patients with a low, medium or high risk of HBV reactivation; however, permanently placing a patient in a definitive category is not always easy. More often, patients move from one category to another during the course of their immunosuppressive treatment; therefore, in many cases, there are no precise indicators or tools for monitoring possible reactivation and establishing the duration and suspension of antiviral prophylaxis. Historically, the sequence of HBV antigens and antibodies and HBV DNA levels has been used to evaluate the different stages of the acute and chronic phases of an HBV infection. In the last few years, new biomarkers, such as anti-HBs and anti-HBc titres, HBV core-related antigen (HBcrAg), ultra-sensitive HBsAg evaluation and HBV RNA, have been used in patients with an HBV infection to evaluate their diagnostic and prognostic potential. The aim of this review is to evaluate the published results on the use of new infection markers in the diagnosis and monitoring of HBV reactivation over the course of immunosuppressive treatments. Moreover, the importance of viral genotypic studies was emphasized, given the diagnostic and therapeutic implications of the mutational profiles of HBsAg during the HBV reactivation phase.
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Parrinello, Nunziatina, Alessandra Romano, Concetta Conticello, Maide Cavalli, Alessia La Fauci, Giuseppina Rizzo, Piera La Cava, et al. "Neutrophils Of Multiple Myeloma Are Dysfunctional and Immunosuppressive." Blood 122, no. 21 (November 15, 2013): 3138. http://dx.doi.org/10.1182/blood.v122.21.3138.3138.
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Abstract Introduction Multiple Myeloma (MM) is a plasma cell malignancy with a well documented immune dysfunction. However the role and function of neutrophils in MM and monoclonal gammopathy of undetermined significance (MGUS) has been poorly investigated. Methods on neutrophils (N) of 65 MM at diagnosis, 74 MGUS and 30 healthy subjects we evaluated, by flow cytometer, phagocytic activity and surface expression of CD64, CD16, CD62L and CD11b, markers of neutrophil activation. We tested also the immunosuppressive properties of N isolated from MGUS or MM patients, through functional assays, based on in vitro co-culture of N isolated from patients and T-lymphocytes from healthy subjects and we evaluated the expression of the immunosuppressive molecule arginase-1 (Arg-1) by RT-PCR. Results Despite no differences in the absolute number of N between MM, MGUS and healthy subjects, we found a functional impairment in MM not evident in MGUS patients. The phagocytic activity of MM-N was significantly reduced compared to healthy subjects-N (p<0.001) and MGUS-N (p<0.0001) and restored after induction chemotherapy (p=0.02). Expression of CD64 was significantly elevated in MM-N compared to MGUS-N or healthy subjects-N (p=0.01 and p= 0.007 respectively) and was inversely correlated with phagocytic activity (p=0,01). No differences were observed among MM, MGUS and healthy subjects for the other surface markers evaluated. MM-N exhibit an increased expression of ARG-1 compared to MGUS and healthy subjects (25.5 vs 6.2 vs 1 fold changes in gene expression, p=0.003), confirmed by functional assay of enzymatic activity of ARG-1, positively correlated with advanced disease. After PHA-P stimulation,T-lymphocytes isolated from healthy subjects missed the expression of activation markers such CD71, CD69, CD25, CD3ζ in the presence of MM-N for 72 hours, and in a less extensive way in the presence of MGUS-N. Conclusion Compared to controls, neutrophils obtained from MM patients have a reduced phagocytic activity, a greater expression of Arg-1 and exhibit an immunosuppressive function on T lymphocytes. Taken together, these findings indicated that neutrophils may contribute to impairment of immune function that characterizes MM patients. Disclosures: No relevant conflicts of interest to declare.
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Awwad, Mohamed H. S., Abdelrahman Mahmoud, Heiko Bruns, Hakim Echchannaoui, Katharina Kriegsmann, Raphael Lutz, Marc S. Raab, et al. "Selective elimination of immunosuppressive T cells in patients with multiple myeloma." Leukemia 35, no. 9 (February 17, 2021): 2602–15. http://dx.doi.org/10.1038/s41375-021-01172-x.
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AbstractElimination of suppressive T cells may enable and enhance cancer immunotherapy. Here, we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8+CD28-CD57+ Tregs in multiple myeloma (MM). SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures. T cells from patients with a high frequency of SLAMF7+CD8+ T cells exhibited decreased immunoreactivity towards the MART-1aa26–35*A27L antigen. A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7+CD8+ T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8+ Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.
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Swatler, Julian, Laura Turos-Korgul, Marta Brewinska-Olchowik, Sara De Biasi, Wioleta Dudka, Bac Viet Le, Agata Kominek, et al. "4-1BBL–containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells." Blood Advances 6, no. 6 (March 17, 2022): 1879–94. http://dx.doi.org/10.1182/bloodadvances.2021006195.
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Abstract Chronic and acute myeloid leukemia evade immune system surveillance and induce immunosuppression by expanding proleukemic Foxp3+ regulatory T cells (Tregs). High levels of immunosuppressive Tregs predict inferior response to chemotherapy, leukemia relapse, and shorter survival. However, mechanisms that promote Tregs in myeloid leukemias remain largely unexplored. Here, we identify leukemic extracellular vesicles (EVs) as drivers of effector proleukemic Tregs. Using mouse model of leukemia-like disease, we found that Rab27a-dependent secretion of leukemic EVs promoted leukemia engraftment, which was associated with higher abundance of activated, immunosuppressive Tregs. Leukemic EVs attenuated mTOR-S6 and activated STAT5 signaling, as well as evoked significant transcriptomic changes in Tregs. We further identified specific effector signature of Tregs promoted by leukemic EVs. Leukemic EVs-driven Tregs were characterized by elevated expression of effector/tumor Treg markers CD39, CCR8, CD30, TNFR2, CCR4, TIGIT, and IL21R and included 2 distinct effector Treg (eTreg) subsets: CD30+CCR8hiTNFR2hi eTreg1 and CD39+TIGIThi eTreg2. Finally, we showed that costimulatory ligand 4-1BBL/CD137L, shuttled by leukemic EVs, promoted suppressive activity and effector phenotype of Tregs by regulating expression of receptors such as CD30 and TNFR2. Collectively, our work highlights the role of leukemic extracellular vesicles in stimulation of immunosuppressive Tregs and leukemia growth. We postulate that targeting of Rab27a-dependent secretion of leukemic EVs may be a viable therapeutic approach in myeloid neoplasms.
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Basak, Sayantani, Anushka Dikshit, Ming Yu, HaYeun Ji, Ching-Wei Chang, and Bingqing Zhang. "92 Single cell and spatial multiplex profiling of immune cell markers in FFPE tumor tissues using the novel RNAscope™ HiPlex v2 in situ hybridization assay." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A101. http://dx.doi.org/10.1136/jitc-2021-sitc2021.092.
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BackgroundThe tumor microenvironment (TME) is highly complex, comprised of tumor cells, immune cells, stromal cells, and extracellular matrix. Understanding spatial interactions between various cell types and their activation states in the TME is crucial for implementing successful immunotherapy strategies against various types of cancer. This study demonstrates a highly sensitive and specific multiplexed technique, the RNAscope HiPlex v2 in situ hybridization (ISH) assay for spatial and transcriptomic profiling of target genes to assess immune regulation in human lung, breast, cervical and ovarian FFPE tumor tissues.MethodsWe have expanded our current RNAscope HiPlex assay capability of iteratively multiplexing up to 12 targets in fixed and fresh frozen samples to include formalin fixed paraffin embedded (FFPE) tissues. The novel FFPE reagent effectively reduces background autofluorescence, improving the signal to noise ratio. We have leveraged this technology to investigate spatial expression of 12 oncology and immuno-oncology target genes, including tumor markers, immune checkpoint markers, immunosuppression markers, immune cell markers and secreted chemokine RNA expression profile within the TME. The targets were simultaneously registered using HiPlex image registration software v2 that enables background subtraction.ResultsWe visualized T cell infiltration and identified T cell subsets within tumors using CD3and CD8 expression and activated T cells by IFNG expression. We further identified subsets of pro- and anti-inflammatory macrophages by CD68 and CD163 expression as well effector cells which secrete chemokines and cytokine. We also detected the hypoxia markers HIF1A and VEGF to elucidate the immunosuppressive state of tumor cells. Preliminary analysis and quantification of the HIF1A expression using HALO® image analysis software showed higher copy numbers in the lung tumor as compared to the other tumors, demonstrating the sensitivity of the assay through differential expression. We additionally showed the differential expression of immune checkpoint markers PDCD1, and CD274 within the TME.ConclusionsUsing a highly sensitive multiplexed RNAscope HiPlex v2 ISH assay, we have demonstrated the capability of this technique to spatially resolve 12 targets in four different tumor types. The FFPE reagent efficiently quenched background autofluorescence in the tissues and identified immune cell signatures within the TME. Quantification of immunosuppressive markers further depicted a differential expression among various tumors. This technology is highly beneficial for investigating complex and spatial tumor-stroma interactions in basic science and translational research. The assay can also provide valuable understanding of the biological crosstalk among various cell types in complex and heterogeneous tissues.
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Dikshit, Anushka, Sayantani Basak, Ching-Wei Chang, Kim Collins, and Michaeline Bunting. "Spatial profiling of immune cell markers in FFPE tumor tissues using the RNAscope&[trade] HiPlex v2 in situ hybridization assay." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 179.17. http://dx.doi.org/10.4049/jimmunol.208.supp.179.17.
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Abstract The tumor microenvironment (TME) is highly complex, comprised of tumor cells, immune cells, stromal cells, and extracellular matrix. This study demonstrates a highly sensitive and specific multiplexed technique, the RNAscope HiPlex v2 in situ hybridization (ISH) assay for spatial and transcriptomic profiling of target genes to assess immune regulation in FFPE tumor tissues. The RNAscope HiPlex v2 assay iteratively multiplexes up to 12 targets in frozen and FFPE tissues. The novel FFPE reagent effectively reduces background autofluorescence, improving the signal to noise ratio. Here we investigate spatial expression of 12 immuno-oncology target genes, including tumor markers, immune checkpoint markers, immunosuppression markers, immune cell markers and secreted chemokines The targets were simultaneously registered using HiPlex image registration software v2 that enables background subtraction. We visualized T cell infiltration and activation within tumors using CD3, CD8 and IFNG expression. Subsets of pro- and anti-inflammatory macrophages were detected by CD68 and CD163 expression Hypoxia markers HIF1A and VEGF indicated immunosuppressive state of tumor cells. Preliminary analysis and quantification of the HIF1A expression using HALO® image analysis showed higher copy numbers in the lung tumor as compared to the other tumors. We additionally showed the differential expression of immune checkpoint markers PDCD1, and CD274 within the TME. Using a highly sensitive multiplexed RNAscope HiPlex v2 ISH assay, 12 key targets were spatially resolved in four different tumor types. The assay can provide valuable understanding of the biological crosstalk among various cell types in complex and heterogeneous tissues.
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Abomaray, Fawaz, Sebastian Gidlöf, and Cecilia Götherström. "Mesenchymal Stromal Cells Are More ImmunosuppressiveIn VitroIf They Are Derived from Endometriotic Lesions than from Eutopic Endometrium." Stem Cells International 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/3215962.
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Endometriosis is an inflammatory disease with predominance of immunosuppressive M2 macrophages in the pelvic cavity that could be involved in the pathology through support and immune escape of ectopic lesions. Mesenchymal stromal cells (MSC) are found in ectopic lesions, and MSC from nonendometriosis sources are known to induce M2 macrophages. Therefore, MSC were hypothesized to play a role in the pathology of endometriosis. The aim was to characterize the functional phenotype of MSC in ectopic and eutopic endometrium from women with endometriosis. Stromal cells from endometriotic ovarian cysts (ESCcyst) and endometrium (ESCendo) were examined if they exhibited a MSC phenotype. Then, ESC were phenotypically examined for protein and gene expression of immunosuppressive and immunostimulatory molecules. Finally, ESC were functionally examined for their effects on monocyte differentiation into macrophages. ESCcystand ESCendoexpressed MSC markers, formed colonies, and differentiated into osteoblasts and adipocytes. Phenotypically, ESCcystwere more immunosuppressive, with significantly higher expression of immunosuppressive molecules. Functionally, ESCcystinduced more spindle-shaped macrophages, with significantly higher expression of CD14 and CD163, both features of M2 macrophages. The results suggest that ESCcystmay be more immunosuppressive than ESCendoand may promote immunosuppressive M2 macrophages that may support growth and reduce immunosurveillance of ectopic lesions.
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Tripathi, Abhishek, Edwin Lin, Roberto Nussenzveig, Mark Yandell, Sumanta K. Pal, and Neeraj Agarwal. "NT5E expression and the immune landscape of prostate cancer (PC): An analysis from The Cancer Genome Atlas database." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e16591-e16591. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e16591.
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e16591 Background: Immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 pathway have shown modest activity in patients with advanced PC. Additional immunosuppressive mechanisms in the PC tumor microenvironment need to be investigated. Increased CD73 (encoded by NT5E) expression results in generation of immunosuppressive adenosine in the tumor microenvironment and has been associated with metastasis and poor survival in PC. Utilizing the TCGA dataset, we investigated the association of NT5E expression with the immune landscape of PC. Methods: RNA-seq data for 331 PC tumor samples and 51 normal adjacent tissue (NAT) samples was downloaded and log2 transformed. Patients were split into low, intermediate, and high expression groups based on NT5E expression (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean) in tumor and NAT. A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged tumor expression of 18 previously validated genes (Ayers et al, 2017). Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes (Charoentong et al, 2017). Immune cell abundance scores and TIS were compared between NT5E expression groups using the Mann-Whitney U test and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression in NAT was not associated with the TIS or expression of immune cell marker genes. In contrast, NT5E expression in tumor tissue correlated positively with TIS (P < 0.001). Compared to tumors with low NT5E expression, those in high NT5E expression group had higher expression of central memory CD4+, effector memory CD8+, type 1 helper, NK and regulatory T (Treg) cell markers. Conclusions: In our analysis, NT5E expression correlated with markers of inflamed tumor phenotype in PC. Although NT5E expression was associated with higher CD8+and CD4+ T cells, concurrent increase in Tregs could inhibit the infiltrating lymphocytes and promote tumor growth. Our findings indicate a possible role for the adenosine pathway as a mediator of immunosuppression in PC and a potential therapeutic target. AT and EL: Equal contribution
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Zoehler, Bernardo, Letícia Fracaro, Lidiane Maria Boldrini-Leite, José Samuel da Silva, Paul J. Travers, Paulo Roberto Slud Brofman, Maria da Graça Bicalho, and Alexandra Cristina Senegaglia. "HLA-G and CD152 Expression Levels Encourage the Use of Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells as an Alternative for Immunosuppressive Therapy." Cells 11, no. 8 (April 14, 2022): 1339. http://dx.doi.org/10.3390/cells11081339.
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Mesenchymal stromal cells (MSCs) have been used in immunosuppressive therapy due to their therapeutic effects, with the HLA-G molecule seeming to play a fundamental role. This work evaluated alternative MSC sources to bone marrow (BM), namely, umbilical cord tissue (UC), adipose tissue (AD) and dental pulp tissue (DP), and the influence of interferon-γ (IFN-γ) and hypoxia on the cultivation of these cells for use in immunosuppression therapies. Expression of costimulatory markers CD40, CD80 and CD86 and immunosuppressive molecules CD152 and HLA-G was analyzed. Lymphocyte inhibition assays were also performed. Sequencing of the HLA-G gene from exons 1 to 5 was performed using next-generation sequencing to determine the presence of alleles. UC-derived MSCs (UCMSCs) expressed higher CD152 and HLA-G1 under standard cultivation. UCMSCs and DP-derived MSCs (DPSCs) secreted similar levels of HLA-G5. All MSC sources inhibited the proliferation of peripheral blood mononuclear cells (PBMCs); growth under regular versus hypoxic conditions resulted in similar levels of inhibition. When IFN-γ was added, PBMC growth was inhibited to a lesser extent by UCMSCs. The HLA-G*01:04:01:01 allele appears to generate a more efficient MSC response in inhibiting lymphocyte proliferation. However, the strength of this conclusion was limited by the small sample size. UCMSCs are an excellent alternative to BM in immunosuppressive therapy: they express high concentrations of inhibitory molecules and can be cultivated without stimuli, which minimizes cost.
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Düchler, Markus, Liliana Czernek, Lukasz Peczek, Wojciech Cypryk, Malgorzata Sztiller-Sikorska, and Malgorzata Czyz. "Melanoma-Derived Extracellular Vesicles Bear the Potential for the Induction of Antigen-Specific Tolerance." Cells 8, no. 7 (July 2, 2019): 665. http://dx.doi.org/10.3390/cells8070665.
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Background: Cancer-induced immunosuppression is antigen-specific rather than systemic and the mechanisms for the antigen specificity are incompletely understood. Here we explore the option that tumor-associated antigens (TAAs) may be transferred to antigen-presenting cells (APCs), together with immunosuppressive molecules, through cancer-derived small extracellular vesicles (sEVs), such as exosomes. Stimulation of a suppressive phenotype in the very same APCs that take up TAAs may yield antigen-specific tolerance. Methods: sEVs isolated from patient-derived or well-established melanoma cell lines were used to demonstrate the transfer of major histocompatibility complex (MHC) molecules to the surface of APCs. The immunosuppressive influence of sEVs was assessed by flow cytometry analysis of activation markers, cytokine expression, and mixed lymphocyte reactions. Results: MHC class I molecules were transferred from melanoma cells to the cell surface of APCs by sEVs. Concomitantly, CD86 and CD40 co-stimulatory molecules were down-regulated and IL-6 production was strongly induced. TGF-β transported by sEVs contributed to the promotion of a suppressive phenotype of APCs. Conclusion: The presented results indicate the existence of a hitherto undescribed mechanism that offers an explanation for antigen-specific tolerance induction mediated by cancer-derived sEVs.
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Gonzalez, Maria Espinoza, Lisa Volk-Draper, Nihit Bhattarai, and Sophia Ran. "Abstract 5626: Acquisition of lymphatic phenotype in bone marrow endothelial progenitors is regulated by immunosuppressive Th2 cytokines." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5626. http://dx.doi.org/10.1158/1538-7445.am2022-5626.
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Abstract Introduction: Myeloid-lymphatic endothelial progenitors (M-LECPs) significantly contribute to expansion of tumor lymphatics and metastasis to lymph nodes. Bone marrow (BM) generated M-LECPs are a subset of M2-type of tumor-associated macrophages (TAMs) that heavily infiltrate breast and other human cancers. The M2-type of TAMs is primarily induced by immunosuppressive Th2 cytokines IL-4, IL-13, and IL-10. The goal of this study was to determine whether Th2 factors also promote the lymphatic phenotype in precursors of M-LECPs. Methods: Mouse BM cells were differentiated into M-LECPs by priming with CSF-1 followed by activation of LPS-TLR4 pathway. Transcripts of IL-4, IL-13, and IL-10 were measured by qPCR, and their proteins secreted into conditioned medium were detected by ELISA. The levels of receptors for Th2 cytokines IL-4, IL-13, and IL-10 as well as for stem cells (CD117, Sca-1), M2-TAMs (CD204, CD206) and lymphatic endothelial cells (Lyve-1, podoplanin, integrin-9a, collectin-12 and stabilin-1) were quantified by qPCR and flow cytometry. Impact of TLR4 induced autocrine IL-10 pathway was determined by analyzing the surface markers and gene profiles of differentiated M-LECPs in the presence of IL-10 blocking or control antibodies. Tumor levels of Th2 cytokines and expression of Th2 receptors in Lyve-1+ progenitors were detected by ELISA and immunofluorescence, respectively. Results: More than 95% of myeloid precursors treated with CSF-1 and LPS upregulated all three Th2 receptors and IL-10 but not IL-4 or IL-13 ligands. All receptors were functional as indicated by upregulation of M2, immunosuppressive, lymphatic and stem markers in cells co-treated with exogenous Th2 ligands as compared with CSF-1 alone. Blocking autocrine IL-10 significantly suppressed both M2-specific and pro-lymphatic differentiation. Tumor-infiltrating M-LECPs expressed Th2 receptors as well as all corresponding ligands including IL-4 and IL-13 that were absent in the BM cells. Conclusion: These data present a novel evidence that activation of immunosuppressive Th2 pathways in BM myeloid precursors induces both the M2-type and lymphatic phenotype. Expansion of lymphatics can enhance tumor immunosuppression by physical removal of immunostimulatory cells. These findings suggest that targeting Th2 pathways can simultaneously relieve immunosuppression and inhibit differentiation of pro-lymphatic progenitors that promote metastasis. Citation Format: Maria Espinoza Gonzalez, Lisa Volk-Draper, Nihit Bhattarai, Sophia Ran. Acquisition of lymphatic phenotype in bone marrow endothelial progenitors is regulated by immunosuppressive Th2 cytokines [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 5626.
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Zhang, Yaqing, Kristee L. Brown, Wei Yan, Zeribe C. Nwosu, Eileen K. Carpenter, Katelyn L. Donahue, Ashley Velez-Delgado, Sion Yang, and Marina Pasca di Magliano. "Abstract PO-129: Targeting CCR1 reprograms tumor associated macrophages in pancreatic cancer." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—129—PO—129. http://dx.doi.org/10.1158/1538-7445.panca21-po-129.
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Abstract The tumor microenvironment of pancreatic ductal adenocarcinoma (PDA) includes abundant fibroblasts and infiltrating immune cells, the latter largely immunosuppressive. We previously showed that targeting regulatory T cell (Treg), a prevalent T cell population in pancreatic cancer, failed to relieve immunosuppression and led to accelerated tumor progression. We discovered that Treg depletion reprogrammed tumor associated fibroblasts and increased immunosuppressive myeloid cell recruitment, an effect that was partially mediated by CCLs/CCR1signaling. Thus, we sought to investigate the potential therapeutic effect of targeting CCR1 in pancreatic cancer. By single cell RNA sequencing, we found CCR1 to be mainly expressed by tumor associated macrophages (TAMs) and neutrophils (or granulocytes) in both human and mouse PDA. We then orthotopically transplanted syngeneic mouse pancreatic cancer cells in CCR1 knockout hosts, and observed reduced tumor growth which was rescued by CD8 T cell depletion. Histological analysis showed elevated Granzyme B expression in infiltrating T cells, as well as an increase in cleaved caspase 3 positive cancer cells in tumors implanted in Ccr1−/− mice. Through cytometry by time of flight (CyTOF) and co-immunofluorescence we also discovered that TAMs in tumors implanted in Ccr1−/− mice expressed less Arginase 1 and CD206 -both markers of immunosuppressive macrophages- compared to TAMs in wild type tumors. Thus, our data is consistent with the notion that tumor associated macrophages lacking CCR1 expression are less immunosuppressive, consequently allowing increased CD8 T cell-mediated anti-tumor immunity. We are currently exploring combination approaches targeting CCR1 in pancreatic cancer. Citation Format: Yaqing Zhang, Kristee L. Brown, Wei Yan, Zeribe C. Nwosu, Eileen K. Carpenter, Katelyn L. Donahue, Ashley Velez-Delgado, Sion Yang, Marina Pasca di Magliano. Targeting CCR1 reprograms tumor associated macrophages in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-129.
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Alam, Shahinul, Saiful Islam, Asma Helen Khan, Mahabubul Alam, Golam Azam, Golam Mustafa, Motahar Hossain, and Mobin Khan. "Clinical Practice Guidance for Management of Anti HBc Positive Patients." Journal of Bangladesh College of Physicians and Surgeons 37, no. 4 (September 30, 2019): 196–201. http://dx.doi.org/10.3329/jbcps.v37i4.43350.
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Hepatitis B core antibody (Anti HBc) is currently considered the most sensitive serological marker for a patient’s history of hepatitis B virus (HBV) infection given its long-term persistence in the bloodstream. The serological pattern of isolated Anti HBc (IAHBc) has been of clinical interest over the past several years.,Thegrowing data of IAHBcsuggestingit as a marker for occult HBV infection (OBI). Occult HBV infection defined as HBV DNA detection in serum or the liver by sensitive diagnostic tests in HBsAg negative individuals with or without serologic markers of previous viral exposure. OBI is especially concerned in blood transfusion (BT), organ donation and reactivation of HBV infection following immunosuppressive therapy. HBV reactivation depends on viral and host factors. The important clinical implications of IAHBcis in the setting of co-infection with hepatitis C virus (HCV), reactivation risk of HBV during directly acting anti viral (DAA) therapy in HCV infection which may lead to progression of liver disease and hepatocellular carcinoma (HCC). Antiviral prophylaxis has been recommended in moderate to high risk of reactivation prior to immunosuppressive and biologics. The main goal of therapy is to improve survival and quality of life by preventing disease progression and to prevent consequent development of HCC. It is proposed to perform Anti-HBc test as a screening test prior to blood transfusion, HBVvaccination, DAA and immunosuppressive therapy in addition to HBsAg screening test.
J Bangladesh Coll Phys Surg 2019; 37(4): 196-201
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Yoshida, Nao, Hiroshi Yagasaki, Yoshiyuki Kosaka, Ryoji Kobayashi, Hiromasa Yabe, Takashi Kaneko, Masahiro Tsuchida, Akira Ohara, Tatsutoshi Nakahata, and Seiji Kojima. "Predicting Response to Immunosuppressive Therapy in Childhood Aplastic Anemia." Blood 112, no. 11 (November 16, 2008): 1049. http://dx.doi.org/10.1182/blood.v112.11.1049.1049.
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Abstract Aplastic anemia (AA) is defined as a pancytopenia caused by bone marrow failure; its pathogenesis is thought to involve autoimmune processes. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CyA) provides response rates of 50–70% for children with AA, but predictive markers of response to therapy have not been well defined. We previously investigated the clinical relevance of HLA, a minor population of paroxysmal nocturnal hemoglobinuria-type cells, and a specific auto-antibody associated with AA in pediatric patients and reported that there was no correlation between these markers and response to therapy (Yoshida N, et al. Br J Haematol, 2008). In the current study, we prospectively evaluated whether clinical and laboratory findings before treatment, including age, sex, interval between diagnosis and treatment, etiology, severity of disease, white blood cell (WBC) count, neutrophil count, hemoglobin level, reticulocyte count, and platelet count, could predict the IST response at 6 months. Subjects included a large population of pediatric AA patients enrolled in a multicenter AA-97 study conducted by the Japan Childhood Aplastic Anemia Study Group. Between October 1997 and September 2006, 312 children (186 boys and 126 girls) younger than 18 years who were newly diagnosed with AA were enrolled in the study and treated with a combination of ATG and CyA. The median age at diagnosis was 8 years (range, 1–17 years). Of the 312 patients, 261 had idiopathic AA, 44 had hepatitis-associated AA, and 7 had AA from other causes. In terms of severity, 156 patients had very severe disease, 107 had severe disease, and 49 had moderate disease. The median interval between diagnosis and treatment was 15 days (range, 1–180 days). The overall response rate was 56%. In multivariate analyses, lower WBC count, shorter interval between diagnosis and therapy, and male sex were predictive markers of better response. Patients with WBC <2500/μl had a significantly higher response rate than those with WBC ≥2500/μl (61 vs. 48%; P=0.008); this was the strongest predictor of response. Notably, response rate was inversely related to the interval between diagnosis and treatment; response rates of patients with an interval between diagnosis and treatment of <30 and ≥30 days were 60% and 43%, respectively (P=0.02). Boys had a better response compared with girls (62 vs. 48%; P=0.02). In conclusion, pretreatment clinical and laboratory findings influence the response rate to IST. Response is well correlated with WBC count rather than neutrophil count or severity of disease. IST should be started as soon as possible after diagnosis of AA, given that the response rate worsens as the interval between diagnosis and treatment increases.
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Vijay-Kumar, Matam, Beng San Yeoh, Vishal Singh, Rachel M. Golonka, and Piu Saha. "Dietary Soluble Fiber Induces HCC in Dysbiotic Mice Through a Spectrum of Immunosuppressive Mediators." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 59.3. http://dx.doi.org/10.4049/jimmunol.202.supp.59.3.
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Abstract Dietary fermentable, soluble fibers (e.g. inulin) are known for promoting health; yet, ~40% of Toll-like receptor 5 deficient (T5KO) mice fed inulin-containing diet (ICD) develop icteric hepatocellular carcinoma (HCC) (Cell, 2018). Specifically, the disease progresses starting with hepatic cholestasis and neutrophilic inflammation at one month, followed by HCC at 6 months of ICD feeding. This diet-driven HCC was dependent on the gut microbiota and was mediated, largely in part, via surfeit production of immunosuppressive short-chain fatty acids (SCFA) and secondary bile acids, presumably as compensatory mechanisms against inflammation in the 40% pre-HCC T5KO mice. What was most striking was the upregulation of systemic bilirubin (a host immunosuppressive metabolite) within one week of ICD feeding. The hyperbilirubinemia was accompanied with an increase in IgA by ~50 and ~10-fold in the serum and liver, respectively, compared to the 60% non-HCC T5KO mice. Markers for anti-tumor T cell exhaustion, i.e. hepatic PD-L1 and layilin, were also upregulated, where the former was elevated within a week of feeding and persisted, while the latter was observed at 6 months. Hepatic immune cell phenotyping after the onset of HCC revealed substantial increase in CD4+FOXP3+PD-L1+T cells and IgA+IL10+PD-L1+Bcells, with the latter denoting a recently identified subset of highly immunosuppressive B cells. Our unprecedented findings collectively demonstrate that dietary fibers and SCFA —which are widely-held to be anti-inflammatory— could potentiate immunosuppression and impede anti-tumor immune surveillance in the tumor microenvironment in mice with gut microbiota dysbiosis.
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Jung, Mi-Yeon, Benjamin Himes, Luz Cumba-Garcia, and Ian Parney. "INNV-32. SUPER-INDUCTION OF IMMUNOSUPPRESSIVE GLIOBLASTOMA EXTRACELLULAR VESICLES BY IFN-γ." Neuro-Oncology 21, Supplement_6 (November 2019): vi137. http://dx.doi.org/10.1093/neuonc/noz175.573.
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Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Median survival is 15 months despite surgery, radiation, and chemotherapy. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. Recently, extracellular vesicles (EVs) have been implicated in GBM-mediated immunosuppression through expression of the immune checkpoint molecule PD-L1. Data from our group has suggested this is predominantly through induction of immunosuppressive monocytes including myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). PD-L1 expression is increased in most nucleated cells following IFN-γ exposure. We, therefore, sought to determine if IFN-γ exposure would result in super-induction of immunosuppressive GBM EVs. EVs were harvested in vitro from matched differentiated and stem-like human GBM cell lines +/- IFN-γ. IFN-γ exposure did not alter EV production or expression of common EV markers but increased PD-L1 expression in EVs from differentiated but not stem-like GBM cells. In keeping with our earlier findings, no direct inhibition of T cell proliferation by stem-like or differentiated GBM EVs was observed regardless of IFN-γ exposure or PD-L1 expression. In contrast, differentiated but not stem-like GBM cell EVs induced MDSC and NCM differentiation from normal monocytes. This was increased following IFN-γ exposure and was dependent upon PD-L1 expression. Monocytes exposed to differentiated but not stem-like GBM cell EVs inhibited T cell proliferation in a similar manner (increased with IFN-γ exposure, decreased with PD-L1 knockdown). Thus, IFN-γ exposure results in super-induction of immunosuppressive EVs from differentiated but not stem-like GBM cells that increase MDSC and NCM differentiation in normal monocytes and increase their ability to inhibit T cell proliferation. These effects are dependent upon PD-L1 up-regulation induced by IFN-γ. This may be an important mechanism GBMs utilize to suppress anti-tumor T cell responses that are typically accompanied by increased IFN-γ expression.
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Dikshit, Anushka, Sayantani Basak, Ching-Wei Chang, Michaeline Bunting, and Kim Collins. "Abstract 3865: Spatial multiplex profiling of immune cell markers in FFPE tumor tissues using the RNAscope™ HiPlex v2 in situ hybridization assay." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3865. http://dx.doi.org/10.1158/1538-7445.am2022-3865.
Full textAbstract:
Abstract The tumor microenvironment (TME) is highly complex, comprised of tumor cells, immune cells, stromal cells, and extracellular matrix. Understanding spatial interactions between various cell types and their activation states in the TME is crucial for implementing successful immunotherapy strategies against various types of cancer. This study demonstrates a highly sensitive and specific multiplexed technique, the RNAscope HiPlex v2 in situ hybridization (ISH) assay for spatial and transcriptomic profiling of target genes to assess immune regulation in human lung, breast, cervical and ovarian FFPE tumor tissues. We have expanded our current RNAscope HiPlex assay capability of iteratively multiplexing up to 12 targets in fixed and fresh frozen samples to include formalin fixed paraffin embedded (FFPE) tissues. The novel FFPE reagent effectively reduces background autofluorescence, improving the signal to noise ratio. We have leveraged this technology to investigate spatial expression of 12 oncology and immuno-oncology target genes, including tumor markers, immune checkpoint markers, immunosuppression markers, immune cell markers and secreted chemokine RNA expression profile within the TME. The targets were simultaneously registered using HiPlex image registration software v2 that enables background subtraction. We visualized T cell infiltration and identified T cell subsets within tumors using CD3 and CD8 expression and activated T cells by IFNG expression. We further identified subsets of pro- and anti-inflammatory macrophages by CD68 and CD163 expression as well effector cells which secrete chemokines and cytokine. We also detected the hypoxia markers HIF1A and VEGF to elucidate the immunosuppressive state of tumor cells. Preliminary analysis and quantification of the HIF1A expression using HALO® image analysis software showed higher copy numbers in the lung tumor as compared to the other tumors, demonstrating the sensitivity of the assay through differential expression. We additionally showed the differential expression of immune checkpoint markers PDCD1, and CD274 within the TME. Using a highly sensitive multiplexed RNAscope HiPlex v2 ISH assay, we have demonstrated the capability of this technique to spatially resolve 12 targets in four different tumor types. The FFPE reagent efficiently quenched background autofluorescence in the tissues and identified immune cell signatures within the TME. Quantification of immunosuppressive markers further depicted differential expression among various tumors. This technology is highly beneficial for investigating complex and spatial tumor-stroma interactions in basic science and translational research. The assay can also provide valuable understanding of the biological crosstalk among various cell types in complex and heterogeneous tissues. Citation Format: Anushka Dikshit, Sayantani Basak, Ching-Wei Chang, Michaeline Bunting, Kim Collins. Spatial multiplex profiling of immune cell markers in FFPE tumor tissues using the RNAscope™ HiPlex v2 in situ hybridization assay [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 3865.
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Kim, Jung-Sik, Min Jung Park, Hyun-Ju Lim, Young-Hee Kim, Sang-Joon Kim, and Chung-Gyu Park. "Endothelial-like cells differentiated from bone marrow-derived mesenchymal stem cells preserve T-cell suppressive function (147.13)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 147.13. http://dx.doi.org/10.4049/jimmunol.186.supp.147.13.
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Abstract Endothelial-like mesenchymal stem cells (EMSCs) differentiated from human mesenchymal stem cells (MSCs) have great potential in cell therapy for ischemic diseases and in tissue engineering for vascular grafts. Although they was proven to stimulate functional blood vessel formation in vivo, it still need to be investigated whether EMSCs harbor immunomodulatory capacity for applying immune-mediated vascular disorders. In this study, therefore, we compared in vivo angiogenic potential of EMSCs with MSCs and studied their immunosuppressive functions. In the phenotype analysis, differentiated EMSC showed several endothelial cell markers including vWF, TGF-beta and Flt-1. In in vitro angiogenesis analysis by using Matrigel and fibrin, they have augmented angiogeneic potential compared to MSCs. Moreover, EMSCs showed neovascularization potential superior to MSCs in subcutaneous transplantation of fibrin-islet-cell composite. In allogeneic mixed lymphocyte reaction, EMSCs showed preserved immunosuppressive function on T cell comparable to that of MSCs. Apoptosis induction and cell-cycle arrest mediated by cell free-culture supernatant were associated with EMSC-mediated T-cell immunosuppression, as evidenced by the increased P27kip and decreased cdk2, cyclin D2 and Bcl-2. These results suggest that ex-vivo expanded EMSC could be a useful source for postnatal neovascularization and for cell-based therapies of tissue damages involving immune reactions.
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Luft, Thomas, Michael Conzelmann, Axel Benner, Michael Rieger, Michael Hess, Ulrich Strohhaecker, Martin Görner, Ute Hegenbart, Anthony D. Ho, and Peter Dreger. "Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease." Blood 110, no. 13 (December 15, 2007): 4535–42. http://dx.doi.org/10.1182/blood-2006-10-049817.
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Graft-versus-host disease (GVHD) is the main complication of allogeneic stem cell transplantation. However, diagnosis of GVHD and evaluation of response to immunosuppressive treatment is sometimes difficult. Since apoptosis is the histopathologic hallmark in GVHD, we investigated whether active GVHD-induced target organ destruction is mirrored by serum levels of the caspase-cleaved neo-epitope of cytokeratin-18 fragments (CK18Fs). Serum CK18F kinetics was monitored by M30 antibody-based enzyme-linked immunosorbent assay (ELISA) in 50 patients who fulfilled histopathologic and/or clinical criteria diagnostic for GVHD. Both intestinal and hepatic GVHD were consistently associated with significant elevations of CK18F levels over baseline. Responses of GVHD to immunosuppressive therapy were paralleled by CK18F decreases, whereas resistant GVHD was characterized by persistent CK18F rises. Clinical conditions that might represent relevant differential diagnoses, such as toxic mucositis, noncomplicated, infection-related diarrhea, and veno-occlusive disease were not associated with CK18F elevations. In conclusion, CK18F monitoring provides a serum marker for quantitative assessment of GVHD-associated apoptotic activity in intestinal and hepatic GVHD. Although apoptosis is not GVHD-specific, CK18Fs may help to distinguish active GVHD from GVHD-unrelated conditions with similar symptoms, and to monitor response to immunosuppressive treatment. Prospective studies are warranted to evaluate how CK18Fs may assist in the diagnosis, grading, and treatment guidance of GVHD.
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Sacerdote, Paola. "Opioids and the immune system." Palliative Medicine 20, no. 8_suppl (January 2006): 9–15. http://dx.doi.org/10.1191/0269216306pm1124oa.
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Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid’s profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent μ-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity to preoperative levels, while in morphine-treated rats NK-lymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity.
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Himes, Benjamin, Cody Nesvick, Helen Li, Mi-Yeon Jung, and Ian Parney. "IMMU-18. GLIOBLASTOMA-DERIVED EXTRACELLULAR VESICLES INDUCE DRAMATIC CHANGES IN THE TRANSCRIPTOMIC LANDSCAPE OF MONOCYTES." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi95. http://dx.doi.org/10.1093/neuonc/noab196.377.
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Abstract Glioblastoma (GBM) is the most common and deadly primary brain tumor. Novel therapeutic strategies are urgently needed to improve outcomes, but a number of disease-specific barriers pose challenges to innovation. Tumor-mediated immunosuppression is one such hurdle, and a growing body of evidence suggests that GBM-derived extracellular vesicles (EVs) play an important role in host immunosuppression. GBM-derived EVs have been shown to induce the formation of immunosuppressive monocytes, including myeloid-derived suppressor cells. Work by our group and others has increasingly shown that these immunosuppressive monocytes are a heterogenous group, and that many constellations of surface markers are inadequate to capture the changes wrought by EVs. In order to better understand the effects of GBM-EVs on monocytes, we conducted RNA-seq analysis on monocytes collected from four healthy donors treated with GBM-derived EVs harvested by ultracentrifugation from the patient-derived BT116 cell line. Following 72h of EV conditioning, total RNA was harvested from treated monocytes and untreated controls. RNA-seq was performed using the Illumina HiSeq4000 platform with paired end index reads. Analysis was performed using RNA STAR and the hg19 ENCODE reference sequence. Differential expression analysis was performed using DESeq2. Genes with a false-discovery rate (FDR)-corrected P value < 0.05 and a log2 fold-change value of >|1| were considered significantly different between groups. Pathway analysis was performed using ClueGO in Cytoscape (GO term fusion on, p< 0.05). Unsupervised clustering analysis of the top 500 most differentially-expressed genes demonstrated grouping of BT116 EV-treated monocytes together versus untreated monocytes. Pathway analysis upregulated genes in pathways important for heparan sulfate proteoglycan synthesis and cholesterol synthesis, which could potentially point to positive regulation of EV uptake. Downregulated pathways included regulation of T cell differentiation and chemoattractant activity, underscoring the induction of a potentially immunosuppressive phenotype by GBM-derived EVs.
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Woolf, Z., M. Swanson, T. Park, A. Brooks, and M. Dragunow. "P10.02 Differentiating microglia and tumour associated macrophages in high grade glioma." Neuro-Oncology 21, Supplement_3 (August 2019): iii40—iii41. http://dx.doi.org/10.1093/neuonc/noz126.142.
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Abstract BACKGROUND Glioblastoma multiforme (GBM) is the most common primary brain tumour that affects adults. This aggressive tumour is invariably fatal, carrying a rapid progression and a dismal median survival period of only 15 months despite multimodal treatment approaches. Central to GBM pathogenesis is the immunosuppressive profile of these tumours. The two cell types that are highly abundant in these tumours and play critical roles in the immunosuppressive niche are the brain’s resident microglia and their peripheral counterparts - tumour associated macrophages (TAMs). Despite microglia and TAMs being ontogenetically distinct, these cells have largely been grouped together in research owing to the previous lack of cell-specific markers. Recent evidence has suggested that although TAMs may hold a predominantly pro-tumoral role, microglia may adopt a more anti-tumoral phenotype. Therefore, the differentiation of these two cell types is critical in elucidating the potentially characteristic roles of these two cell types in GBM pathogenesis. MATERIAL AND METHODS Tissue sections from resected low- and high-grade glioma tumours, along with epilepsy tissue (control), were used for immunohistochemistry (IHC) staining of macrophage pan-makers (Iba1, CD45, PU.1) and microglial-specific markers (TMEM119, P2RY12). Marker co-localisation was then used to differentiate microglia from TAMs. We further investigated a wider subset of cell-specific markers using multicolour flow cytometry and immunocytochemical staining of isolated cells from patient tissue samples. RESULTS Immunofluorescent staining of glioma and epilepsy tissue revealed two clear populations of cells; one population displayed long processes and co-labelling for both pan- and microglial-specific markers, whilst the other population displayed an amoeboid phenotype with only pan-maker staining. Preliminary analysis comparing microglia/TAM populations in low-grade, high-grade and epilepsy tissue suggests a clear difference in the proportions of these cells. CONCLUSION Our work complements RNA-Seq studies, showing that TMEM119 and P2RY12, alongside other markers, can indeed identify two distinct myeloid cell populations within glioma tissue. This provides a strong basis for further study where we aim to elucidate the respective roles of microglia and TAMs within tumours. Ultimately, this may hold the potential for differential targeting of these cells using immunotherapies.
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Wolfram, Dolores, Evi M. Morandi, Nadine Eberhart, Theresa Hautz, Hubert Hackl, Bettina Zelger, Gregor Riede, et al. "Differentiation between Acute Skin Rejection in Allotransplantation and T-Cell Mediated Skin Inflammation Based on Gene Expression Analysis." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/259160.
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Advances in microsurgical techniques and immunosuppressive medication have rendered transplantation of vascularized composite allografts possible, when autologous tissue is neither available nor sufficient for reconstruction. However, skin rejection and side effects of long-term immunosuppression still remain a major hurdle for wide adoption of this excellent reconstructive technique. Histopathologic changes during acute skin rejection in vascular composite allotransplantation often mimic inflammatory skin disorders and are hard to distinguish. Hence, the identification of diagnostic and therapeutic markers specific for skin rejection is of particular clinical need. Here we present novel markers allowing for early differentiation between rejection in hind limb allotransplantation and contact hypersensitivity. Assessment of Ccl7, Il18, and Il1b expression is most indicative of distinguishing skin rejection from skin inflammatory disorders. Gene expression levels varied significantly across skin types and regions, indicating localization specific mechanism of leukocyte migration and infiltration. Expression of Il12b, Il17a, and Il1b gene expression levels differed significantly between rejection and inflammation, independent of the skin type. In synopsis of the RNA expression profile and previously assessed protein expression, the Il1 family appears as a promising option for accurate skin rejection diagnosis and, as a following step, for development of novel rejection treatments.
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Kim, Daeseung, Jeong Seon Kim, Inyoung Cheon, Seo Ree Kim, Sang Hoon Chun, Jae Jun Kim, Sieun Lee, et al. "Identification and Characterization of Cancer-Associated Fibroblast Subpopulations in Lung Adenocarcinoma." Cancers 14, no. 14 (July 18, 2022): 3486. http://dx.doi.org/10.3390/cancers14143486.
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Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells and other stromal cell types. CAFs are composed of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, and immunosuppressive CAFs. In this study, we sought to identify subpopulations of CAFs isolated from human lung adenocarcinomas and describe their transcriptomic and functional characteristics through single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatics analyses. Cell trajectory analysis of combined total and THY1 + CAFs revealed two branching points with five distinct branches. Based on Gene Ontology analysis, we denoted Branch 1 as “immunosuppressive”, Branch 2 as “neoantigen presenting”, Branch 4 as “myofibroblastic”, and Branch 5 as “proliferative” CAFs. We selected representative branch-specific markers and measured their expression levels in total and THY1 + CAFs. We also investigated the effects of these markers on CAF activity under coculture with lung cancer cells. This study describes novel subpopulations of CAFs in lung adenocarcinoma, highlighting their potential value as therapeutic targets.
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Taherian, Mehran, Hua Wang, and Huamin Wang. "Pancreatic Ductal Adenocarcinoma: Molecular Pathology and Predictive Biomarkers." Cells 11, no. 19 (September 29, 2022): 3068. http://dx.doi.org/10.3390/cells11193068.
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Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance to conventional treatment modalities, targeted therapies, and immunotherapies. PDACs are a heterogenous group of malignant epithelial neoplasms with various histomorphological patterns and complex, heterogenous genetic/molecular landscapes. The newly proposed molecular classifications of PDAC based on extensive genomic, transcriptomic, proteomic and epigenetic data have provided significant insights into the molecular heterogeneity and aggressive biology of this deadly disease. Recent studies characterizing the tumor microenvironment (TME) have shed light on the dynamic interplays between the tumor cells and the immunosuppressive TME of PDAC, which is essential to disease progression, as well as its resistance to chemotherapy, newly developed targeted therapy and immunotherapy. There is a critical need for the development of predictive markers that can be clinically utilized to select effective personalized therapies for PDAC patients. In this review, we provide an overview of the histological and molecular heterogeneity and subtypes of PDAC, as well as its precursor lesions, immunosuppressive TME, and currently available predictive molecular markers for patients.
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Morozov, S. L., and V. V. Dlin. "Markers of steroid resistance of the primary nephrotic syndrome in children." Practical medicine 19, no. 1 (2021): 15–21. http://dx.doi.org/10.32000/2072-1757-2021-1-15-21.
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The global task of the recent decade is to search for clinical and laboratory markers accurately showing a patient’s reaction to steroid therapy and other immunosuppressive drugs. It is important the applied methods and tests to be non-invasive and simple to use. The article considers various biomarkers used to verify the type of nephrotic syndrome depending on the sensitivity to steroid therapy. Besides the common markers, which are used in clinical practice or have shown a significant result, the work highlights the molecular- genetic markers of resistance to steroid therapy, which are of special clinical importance today. Also, the article presents authors’ own results in diagnosing the steroid resistance of the primary nephrotic syndrome.
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Terzuoli, Erika, Cristiana Bellan, Sara Aversa, Valerio Ciccone, Lucia Morbidelli, Antonio Giachetti, Sandra Donnini, and Marina Ziche. "ALDH3A1 Overexpression in Melanoma and Lung Tumors Drives Cancer Stem Cell Expansion, Impairing Immune Surveillance through Enhanced PD-L1 Output." Cancers 11, no. 12 (December 6, 2019): 1963. http://dx.doi.org/10.3390/cancers11121963.
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Melanoma and non-small-cell lung carcinoma (NSCLC) cell lines are characterized by an intrinsic population of cancer stem-like cells (CSC), and high expression of detoxifying isozymes, the aldehyde dehydrogenases (ALDHs), regulating the redox state. In this study, using melanoma and NSCLC cells, we demonstrate that ALDH3A1 isozyme overexpression and activity is closely associated with a highly aggressive mesenchymal and immunosuppressive profile. The contribution of ALDH3A1 to the stemness and immunogenic status of melanoma and NSCLC cells was evaluated by their ability to grow in 3D forming tumorspheres, and by the expression of markers for stemness, epithelial to mesenchymal transition (EMT), and inflammation. Furthermore, in specimens from melanoma and NSCLC patients, we investigated the expression of ALDH3A1, PD-L1, and cyclooxygenase-2 (COX-2) by immunohistochemistry. We show that cells engineered to overexpress the ALDH3A1 enzyme enriched the CSCs population in melanoma and NSCLC cultures, changing their transcriptome. In fact, we found increased expression of EMT markers, such as vimentin, fibronectin, and Zeb1, and of pro-inflammatory and immunosuppressive mediators, such as NFkB, prostaglandin E2, and interleukin-6 and -13. ALDH3A1 overexpression enhanced PD-L1 output in tumor cells and resulted in reduced proliferation of peripheral blood mononuclear cells when co-cultured with tumor cells. Furthermore, in tumor specimens from melanoma and NSCLC patients, ALDH3A1 expression was invariably correlated with PD-L1 and the pro-inflammatory marker COX-2. These findings link ALDH3A1 expression to tumor stemness, EMT and PD-L1 expression, and suggest that aldehyde detoxification is a redox metabolic pathway that tunes the immunological output of tumors.
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Castelli, Mauro, Patrizio Romano, Giuseppe Atlante, Maurizio Pozzi, and Umberto Ferrini. "Immunosuppressive Acidic Protein (Iap) and Ca 125 Assays in Detection of Human Ovarian Cancer: Preliminary Results." International Journal of Biological Markers 2, no. 3 (September 1987): 187–90. http://dx.doi.org/10.1177/172460088700200310.
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Serum levels of the immunosuppressive acidic protein (IAP) and CA-125 were measured in 45 patients with ovarian tumors (30 malignant and 15 benign) before surgery. Concentrations of both markers were slightly increased in benign forms but still within the upper limit for controls. The sensitivity of IAP in detecting ovarian cancer was higher than CA-125 (83.4% versus 76.7%). Five false negatives were observed in IAP assay and seven for CA-125. Parallel determination of both markers, however, improved the diagnostic accuracy up to 90.0% of the total malignant cases. Combined measurements of circulating IAP and CA-125 are therefore recommended in the detection of ovarian cancers.
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Lee, Juyeun, Nogi Park, Joo Youn Park, Sunghyun Yoon, Juw Won Park, Stephen B. Pruett, and Keun Seok Seo. "Suboptimal stimulation with staphylococcal enterotoxin C1 induces immunosuppressive CD4+CD25+ regulatory T cells by differential expression of FOXP3 isoforms." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 117.22. http://dx.doi.org/10.4049/jimmunol.200.supp.117.22.
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Abstract Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and preventing excessive tissue damage upon immune activation. However, pathogens could exploit Tregs for their successful pathogenesis. We demonstrated that immunosuppressive CD4+CD25+FOXP3+ Tregs were induced by staphylococcal enterotoxin (SE) produced by an important human pathogen, Staphylococcus aureus. CD4+CD25+FOXP3+ T cells were induced from stimulation with SEC1 at a high (1 μg/ml) and low (1 ng/ml) concentrations that induced optimal stimulation and suboptimal stimulation, respectively. However, CD4+CD25+FOXP3+ T cells induced from suboptimal stimulation were functionally immunosuppressive, not from optimal stimulation. Immunosuppressive CD4+CD25+FOXP3+ T cells induced from suboptimal stimulation showed typical Treg surface markers such as CTLA-4, GITR, TNFR2, and CD45RO and produced immunomodulatory cytokines such as TGF-β and IL-10. However, suppression was mainly mediated by galectin-1 in a contact-dependent manner. We found that CD4+CD25+ Tregs from suboptimal stimulation highly express FOXP3 isoform lacking exon 2 (ΔE2) and partially lacking exon3 (ΔpE3) preferably localized to the nucleus, compared to those from optimal stimulation. Lentiviral transduction of FOXP3 isoforms (full length, ΔE2, ΔpE3) to Jurkat T cells did not result in immunosuppressive function. By contrast, when cultured in the media generated from suboptimal T cell stimulation, transduced Jurkat T cells became more immunosuppressive in an order of ΔE2 ΔpE3, and full length FOXP3. These results suggest that soluble factors generated from suboptimal T cell proliferation play an important role in induction of immunosuppressive Tregs.
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Pankewycz, Oleh, Hans Minderman, Paul Wallace, Lin Feng, and Mark R. Laftavi. "A novel method to assess the level of immunosupression in transplant patients using Amnis ImageStream technology (141.24)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 141.24. http://dx.doi.org/10.4049/jimmunol.182.supp.141.24.
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Abstract Contemporary immunosuppressive protocols rely on drug dosing guidelines gleaned from large clinical trials, but the effect of this therapy in a transplant recipient remains difficult to predict. To assess global immunosuppression in individual patients, we measured the degree to which NFkB translocation in peripheral T cells was impaired by conventional immunosuppressive therapy. NFkB is a ubiquitously expressed transcription factor normally sequestered in the cytoplasm. Upon activation, NFkB inhibitors are degraded, releasing NFkB to translocate to the nucleus. The abundance of NFkB in the nucleus vs. the cytosol reflects the activation state of a particular cell type. Peripheral blood cells were isolated from 17 subjects, stimulated in culture for 24 hrs with PMA and ionomycin and stained for T cell surface markers and the major intracellular isoform of NFkB, RelA or p65. Using Amnis Imagestream technology, we compared nuclear NFkB in resting and activated CD3, CD4 and CD8 T cell subsets. Compared to normal controls (n=8), transplant recipients on tacrolimus, MPA and prednisone showed reduced translocation of NFkB to the nucleus. Patients with stable allograft function (n=5) had a 36-75% reduction in nuclear NFkB translocation in all 3 T cell subsets. In contrast, patients with acute rejection (n=2) had an increase in ability to translocate NFkB in CD3 and CD8 cells and only a 9% suppression in CD4 cells. Patients with viral infections (n=2) had severely compromised NFkB translocation with 100% suppression in CD3 and CD4 subsets and 92% suppression in CD8 T cells. NFkB inhibition strongly correlates with overall immunosuppression and clinical outcomes. The novel Amnis Imagestream assay may be a useful guide to individualizing immune therapy or directing minimization strategies. (unfunded)
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Sierra-Filardi, Elena, Amaya Puig-Kröger, Francisco J. Blanco, Concha Nieto, Rafael Bragado, M. Isabel Palomero, Carmelo Bernabéu, Miguel A. Vega, and Angel L. Corbí. "Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers." Blood 117, no. 19 (May 12, 2011): 5092–101. http://dx.doi.org/10.1182/blood-2010-09-306993.
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Abstract M-CSF favors the generation of folate receptor β–positive (FRβ+), IL-10–producing, immunosuppressive, M2-polarized macrophages [M2 (M-CSF)], whereas GM-CSF promotes a proinflammatory, M1-polarized phenotype [M1 (GM-CSF)]. In the present study, we found that activin A was preferentially released by M1 (GM-CSF) macrophages, impaired the acquisition of FRβ and other M2 (M-CSF)–specific markers, down-modulated the LPS-induced release of IL-10, and mediated the tumor cell growth–inhibitory activity of M1 (GM-CSF) macrophages, in which Smad2/3 is constitutively phosphorylated. The contribution of activin A to M1 (GM-CSF) macrophage polarization was evidenced by the capacity of a blocking anti–activin A antibody to reduce M1 (GM-CSF) polarization markers expression while enhancing FRβ and other M2 (M-CSF) markers mRNA levels. Moreover, an inhibitor of activin receptor-like kinase 4/5/7 (ALK4/5/7 or SB431542) promoted M2 (M-CSF) marker expression but limited the acquisition of M1 (GM-CSF) polarization markers, suggesting a role for Smad2/3 activation in macrophage polarization. In agreement with these results, expression of activin A and M2 (M-CSF)–specific markers was oppositely regulated by tumor ascites. Therefore, activin A contributes to the proinflammatory macrophage polarization triggered by GM-CSF and limits the acquisition of the anti-inflammatory phenotype in a Smad2-dependent manner. Our results demonstrate that activin A–initiated Smad signaling skews macrophage polarization toward the acquisition of a proinflammatory phenotype.
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Zhou, Jingying, Man Liu, Hanyong Sun, Yu Feng, Liangliang Xu, Anthony W. H. Chan, Joanna H. Tong, et al. "Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy." Gut 67, no. 5 (September 22, 2017): 931–44. http://dx.doi.org/10.1136/gutjnl-2017-314032.
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ObjectiveMyeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).DesignImmunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.ResultsTumour-infiltrating CD11b+CD33+HLA-DR− MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR− MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon γ+tumour necrosis factor-α+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.ConclusionOur results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
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Nafia, Imane, Assia Chaibi, Christophe Rey, Jean-Philippe Guegan, Alban Bessede, Coriolan Lebreton, and Antoine Italiano. "Abstract 2527: Ovarian cancer ascites display altered immune environment featured by enhanced soluble factors and suppressive cellular context." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2527. http://dx.doi.org/10.1158/1538-7445.am2022-2527.
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Abstract Background: Tumor microenvironment (TME) of epithelial ovarian cancer is unique among solid tumors as tumor cells create their "malignant ascites" TME. These ascites, acting as a complex mixture of soluble factors and cell components, are known to be rich in macrophages which were suggested to skew to a M2-like phenotype involved in resistance and metastases. However, while macrophages can adopt different phenotypes, it's now postulated that tumor-associated macrophages (TAM) from ovarian cancer patient ascites may even acquire mixed M1/M2 properties, providing a particular pro-inflammatory and tumor-promoting microenvironment. Characterization of cell composition along with the growth factors present in the microenvironment is thus crucial to understand ovarian cancer biology and more particularly the immunosuppressive pathways that would underlie the altered immune cell activity. Methods & Results: Through flow cytometry-based marker expression analysis and quantitation of soluble mediators in ovarian cancer ascites, we investigated here the cell component nature as well as the presence of several growth factors. While these ascites were interestingly enriched in major "immunosuppressive" cell subsets including T and myeloid populations, TAM were intriguingly shown to display a mixed phenotype characterized by high expression of CD163, unrelated to M1/M2 categorization since also expressing Arg1, CD80, and iNOS markers. The immunosuppressive phenotype was also linked to IL6, LIF and IL10 among other factors present in the ascitic environment. In order to assess their role in the occurrence of such an immunosuppressive cell status, soluble mediators were then investigated on healthy monocytes undergoing M1 polarization. We demonstrated that, while LIF did not directly affect IL6 and IL10 levels released by the cells, interestingly IL6 alone or in co-presence with LIF decreased IL6 supernatant content, with respect to the control. These changes were concomitant with a decrease and increase in the expression of CD80 and CD163, respectively. Furthermore, CD14 and CD206 were found to increase in the presence of IL6+/-LIF. Conclusion: All these data highlight a switching activity of IL6 skewing cells from M1 polarization and resulting in a proper macrophage phenotype exhibiting a mixed M1/M2 status and would suggest these ascite-containing factors as keys conferring an immunosuppressive cell phenotype. Altogether, these translational findings highlight ovarian patient-derived ascites as a valuable tool to understand the mechanisms of suppression and to allow for the identification of novel markers to develop innovative targeted therapies. Citation Format: Imane Nafia, Assia Chaibi, Christophe Rey, Jean-Philippe Guegan, Alban Bessede, Coriolan Lebreton, Antoine Italiano. Ovarian cancer ascites display altered immune environment featured by enhanced soluble factors and suppressive cellular context [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 2527.