scholarly journals Tumor-associated macrophages mediate immune suppression by secreting PD-L1+ exosomes in epithelial ovarian cancer

2019 ◽  
Author(s):  
Xingchen Zhou ◽  
Xiaoli Wu ◽  
Xiaoduan Li ◽  
Yi Zhang ◽  
Xipeng Wang
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Immune Suppression ◽  
Ovarian Tumor ◽  
Tumor Associated Macrophages ◽  
Programmed Death ◽  
Benign Ovarian Tumor

Abstract Purpose: To study the role of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway in patients with epithelial ovarian cancer (EOC). Methods: A total of 10 EOC specimens and 10 benign ovarian tumor were obtained from surgery and the pathological type. We used the methods of immunofluorescence confocal microscopy, western blot, MTT assay, apoptosis detection and co-culture to verify the aim of the research. Results: In the present study, it was validated that the number of PD-L1+ tumor-associated macrophages (TAMs) per field was significantly increased in EOC tissues compared with benign ovarian tumor tissues. Furthermore, it was demonstrated that PD-L1 was expressed on the membrane of TAM-derived exosomes, which may inhibit the proliferation and induce the apoptosis of T cells by activating the caspase 3 signaling pathway. The analysis of the supernatant of T cells co-cultured with TAM drived exosome revealed that the levels of pro-inflammatory cytokines and tumor necrosis factor α decreased compared with those T cells co-cultured with monocyte drived exosome. However, the expression of the immuno-suppressive cytokine, interleukin 10 and markers of T cell exhaustion (the inhibitory molecule lymphocyte activated gene-3, T-cell immunoglobulin and mucin domain-containing protein-3 and PD-1) increased. Conclusions: The present study demonstrated that the M2-derived exosomes regulate immune suppression in the EOC microenvironment. The findings of the present study provide a theoretical basis for future target therapy on exosomes from immune cells to treat EOC.

scholarly journals Subsequent Development of Epithelial Ovarian Cancer After Ovarian Surgery for Benign Ovarian Tumor: A Population-Based Cohort Study

2020 ◽  
Vol Volume 12 ◽  
pp. 637-649 ◽  
Author(s):  
Chen-Yu Huang ◽  
Wen-Hsun Chang ◽  
Hsin-Yi Huang ◽  
Chao-Yu Guo ◽  
Yiing-Jenq Chou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cohort Study ◽  
Epithelial Ovarian Cancer ◽  
Ovarian Tumor ◽  
Subsequent Development ◽  
Population Based ◽  
Benign Ovarian Tumor ◽  
Ovarian Surgery

scholarly journals Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1832 ◽  
Author(s):  
Grégory Verdeil ◽  
Toby Lawrence ◽  
Anne-Marie Schmitt-Verhulst ◽  
Nathalie Auphan-Anezin
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Immune Suppression ◽  
Immune Cells ◽  
Nuclear Translocation ◽  
Effector Memory ◽  
Negative Effects ◽  
Tumor Associated Macrophages ◽  
Term Survival

Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients.

scholarly journals Serum Levels of S100A11 and MMP-9 in Patients with Epithelial Ovarian Cancer and Their Clinical Significance

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Wenjing Li ◽  
Zhumei Cui ◽  
Yan Kong ◽  
Xiangyu Liu ◽  
Xiangyu Wang
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Significance ◽  
Ovarian Tumor ◽  
Tumor Staging ◽  
Serum Levels ◽  
Clinicopathological Characteristics ◽  
Chemotherapy Response ◽  
Healthy Women ◽  
Benign Ovarian Tumor

Objective. To investigate the serum levels of calgizzarin (S100A11) and matrix metalloproteinase-9 (MMP9) in patients with epithelial ovarian cancer (EOC) and determine their clinical significance. Methods. Serum levels of S100A11 and MMP9 were detected in patients with EOC, patients with benign ovarian tumor, and healthy women. The correlation between the two markers and clinicopathological characteristics of ovarian cancer was analysed. Results. The serum levels of S100A11 and MMP-9 in patients with EOC were higher than those in patients with benign ovarian tumor and in healthy women, and the expression levels of S100A11 and MMP-9 were positively correlated. S100A11 and MMP-9 were correlated with tumor staging, postoperative residual foci, ascites volume, serum CA125 level, chemotherapy response, and lymph node metastasis, while S100A11 and MMP-9 were not associated with the bilevel classification, histological type, age, and degree of differentiation. Conclusion. S100A11 and MMP-9 were both highly expressed in the serum of patients with EOC and were associated with cancer development, invasion, and metastasis. Therefore, they can be used as an important reference maker in the diagnosis and treatment of ovarian cancer.

PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3220-3224 ◽  
Author(s):  
Ryo Yamamoto ◽  
Momoko Nishikori ◽  
Toshio Kitawaki ◽  
Tomomi Sakai ◽  
Masakatsu Hishizawa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Signaling Pathway ◽  
Ligand Interaction ◽  
Tumor Immune Evasion ◽  
T Cell Lymphomas ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immunosuppressive Microenvironment

Abstract Programmed death-1 (PD-1)–PD-1 ligand (PD-L) signaling system is involved in the functional impairment of T cells such as in chronic viral infection or tumor immune evasion. We examined PD-L expression in lymphoid cell lines and found that they were up-regulated on Hodgkin lymphoma (HL) and several T-cell lymphomas but not on B-cell lymphomas. PD-L expression was also demonstrated in primary Hodgkin/Reed-Sternberg (H/RS) cells. On the other hand, PD-1 was elevated markedly in tumor-infiltrating T cells of HL, and was high in the peripheral T cells of HL patients as well. Blockade of the PD-1 signaling pathway inhibited SHP-2 phosphorylation and restored the IFN-γ–producing function of HL-infiltrating T cells. According to these results, deficient cellular immunity observed in HL patients can be explained by “T-cell exhaustion,” which is led by the activation of PD-1–PD-L signaling pathway. Our finding provides a potentially effective immunologic strategy for the treatment of HL.

Title Prognosis Significance of ZEB2 and TGF-β1 as well as Other Clinical Characteristics in Epithelial Ovarian Cancer

2017 ◽  
Vol 27 (7) ◽  
pp. 1343-1349 ◽  
Author(s):  
Zhen Yan ◽  
Xiaoyu Tian ◽  
Ruifang Wang ◽  
Xiaolin Cheng ◽  
Jianqiang Mi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Ovarian Tumor ◽  
Clinical Characteristics ◽  
Transforming Growth Factor ◽  
Cox Regression ◽  
Figo Stage ◽  
Start Time ◽  
Benign Ovarian Tumor ◽  
Tgf Β1

ObjectiveThis study aimed to evaluate the prognosis significance of zinc-finger E-box binding homeobox 2 (ZEB2) and transforming growth factor β1 (TGF-β1) as well as other clinical characteristics in epithelial ovarian cancer (EOC).MethodsThis retrospective study examined the expressions of ZEB2 and TGF-β1 in 64 EOC specimens, 36 benign ovarian tumor specimens, and 28 normal ovarian specimens by immunohistochemistry. The correlation of the expressions of ZEB2 and TGF-β1 was analyzed by the Spearman rank correlation analysis. The Kaplan-Meier method was used to construct crude survival curves, and the prognostic roles of ZEB2 and TGF-β1 as well as clinical characteristics were evaluated by Cox proportional hazards regression analysis.ResultsThe positive expression rates of ZEB2 and TGF-β1 were increased in EOC specimens compared with benign ovarian tumor and normal ovary specimens (P < 0.05), and ZEB2 expression was positively correlated with TGF-β1 expression (r = 0.538, P = 0.000). In addition, the overall survival rate of EOC patients was associated with the expressions of ZEB2 and TGF-β1, age, differentiated grade, International Federation of Gynecology and Obstetrics (FIGO) stage, preoperative serum CA125 level, postoperative start time of chemotherapy, and treatment course (all P < 0.05). Multivariate Cox regression demonstrated that FIGO stage (P = 0.033), TGF-β1 expression (P = 0.043), postoperative start time of chemotherapy (P = 0.009), and treatment course (P = 0.000) were prognostic factors for EOC.ConclusionsZEB2 and TGF-β1 may promote EOC progression, and FIGO stage, TGF-β1 expression, postoperative start time of chemotherapy, and treatment course may be associated with the prognosis of EOC.

scholarly journals A Pilot Study of Circulating MicroRNA-125b as a Diagnostic and Prognostic Biomarker for Epithelial Ovarian Cancer

2016 ◽  
Vol 27 (1) ◽  
pp. 3-10 ◽  
Author(s):  
Tao Zhu ◽  
Wen Gao ◽  
Xi Chen ◽  
Ying Zhang ◽  
Meijuan Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Patients ◽  
Ovarian Tumor ◽  
Patient Survival ◽  
Chain Reaction ◽  
Tumor Patients ◽  
Serum Mirna ◽  
Benign Ovarian Tumor ◽  
Polymerase Chain

ObjectiveEarly diagnosis of epithelial ovarian cancer is critical for patient survival. The objective of this pilot study is to identify a circulating micro (mi)RNA as a potential biomarker for epithelial ovarian cancer.MethodsA total of 135 epithelial ovarian cancer patients and 54 benign ovarian tumor patients were recruited for this study. Using customized TaqMan low density miRNA arrays, we first screened expression levels of 48 miRNAs in sera from 18 epithelial ovarian cancer patients and 16 benign ovarian tumor patients. The most significantly and differentially expressed miRNA was then further examined in all serum samples using real-time polymerase chain reaction. Its expression was further analyzed in relationship with clinicopathological factors and patient survival.ResultsArray screening data showed that expression levels of serum miRNA-20a, miRNA-125b, miRNA-126, miRNA-355, and let-7c were significantly different between malignant and benign ovarian tumor patients. Subsequent real-time polymerase chain reaction results showed that serum miRNA-125b levels were significantly higher in epithelial ovarian cancer patients compared to benign controls. Moreover, serum miRNA-125b levels were significantly higher in ovarian cancer patients in early stages I and II, and in patients having no residual tumor following surgery, but were not associated with differentiation and histological types of ovarian cancer. Notably, the higher level of miR-125b was significantly positively correlated with progression-free survival (P= 0.035) and marginally, with overall survival (P =0.069).ConclusionsmiRNA-125b plays an important role in the pathogenesis and progression of epithelial ovarian cancer. Circulating miRNA-125b has the potential to become a novel biomarker for early diagnosis and prognosis prediction of epithelial ovarian cancer.

scholarly journals Relationship between PD-L1 expression, CD8+ T-cell infiltration and prognosis in intrahepatic cholangiocarcinoma patients

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Min Deng ◽  
Shao-Hua Li ◽  
Xu Fu ◽  
Xiao-Peng Yan ◽  
Jun Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Intrahepatic Cholangiocarcinoma ◽  
Patient Survival ◽  
Disease Free Survival ◽  
Cd8 T Cell ◽  
Future Research ◽  
Programmed Death ◽  
Expression Rate

Abstract Background Programmed death- ligand 1 (PD-L1) seems to be associated with the immune escape of tumors, and immunotherapy may be a favorable treatment for PD-L1-positive patients. We evaluated intrahepatic cholangiocarcinoma (ICC) specimens for their expression of PD-L1, infiltration of CD8+ T cells, and the relationship between these factors and patient survival. Methods In total, 69 resections of ICC were stained by immunohistochemistry for PD-L1, programmed death factor-1 (PD-1), and CD8+ T cells. CD8+ T-cell densities were analyzed both within tumors and at the tumor-stromal interface. Patient survival was predicted based on the PD-L1 status and CD8+ T-cell density. Results The expression rate of PD-L1 was 12% in cancer cells and 51% in interstitial cells. The expression rate of PD-1 was 30%, and the number of CD8+ T-cells increased with the increase of PD-L1 expression (p < 0.05). The expression of PD-L1 in the tumor was correlated with poor overall survival(OS) (p = 0.004), and the number of tumor and interstitial CD8+ T-cells was correlated with poor OS and disease-free survival (DFS) (All p < 0.001). Conclusions The expression of PD-L1 in the tumor is related to poor OS, and the number of tumor or interstitial CD8+ T-cells is related to poor OS and DFS. For patients who lose their chance of surgery, PD-L1 immunosuppressive therapy may be the focus of future research as a potential treatment.

186 Distinct immune signatures predicting clinical response to PD-1 blockade therapy in gynecological cancers revealed by high-dimensional immune profiling

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A200-A200
Author(s):  
Yuki Muroyama ◽  
Yuki Muroyama ◽  
Sasikanth Manne ◽  
Alexandar Huang ◽  
Divij Mathew ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Endometrial Cancer ◽  
T Cell ◽  
Clinical Response ◽  
Cancer Patients ◽  
T Cell Response ◽  
High Dimensional ◽  
Uterine Endometrial Cancer ◽  
Immune Profiling

BackgroundAlthough immune checkpoint blockade revolutionized cancer therapy, response rates have been mixed in gynecological malignancies. While uterine endometrial cancer with high microsatellite instability (MSIHI) and high tumor mutational burden (TMB) respond robustly to checkpoint blockade, high-grade serous ovarian cancer (HGSOC) with low TMB respond modestly. Currently, there has been no known immune signature or T cell phenotype that predicts clinical response in gynecological tumors.MethodsTo dissect the immune landscape and T cell phenotypes in gynecological cancer patients receiving PD-1 blockade, we used high-dimensional cytometry (flow cytometry and mass cytometry (CyTOF)). We performed longitudinal deep immune profiling of PBMC from patients with recurrent uterine endometrial cancer receiving single-arm nivolumab, and HSGOC patients receiving neoadjuvant nivolumab plus platinum-based chemotherapy prior to debulking surgery.ResultsChemotherapy-resistant MSI-H uterine cancer patients treated with nivolumab had a proliferative T cell response 2–4 weeks post PD-1 blockade, consistent with responses seen in high TMB melanoma and lung cancer. The responding Ki67+ CD8 T cell population was largely CD45RAloCD27hi or CD45RAloCD27lo and highly expressed PD1, CTLA-4, and CD39, consistent with the phenotype of exhausted T cells (TEX). These exhausted-like cells are enriched in responders, whereas early expansion Tregs are enriched in non-responders. Unlike patients with uterine endometrial cancer, patients with TMBlo ovarian cancer did not have a clear proliferative CD8 T cell response after neoadjuvant nivolumab plus chemotherapy treatment, suggesting systemic immune suppression. At baseline, ovarian cancer without recurrence have more terminally differentiated effector-like CD8 T cells, and patients with recurrence have more naive-like cells. Thus, both high and low TMB gynecological tumors have distinct immune landscapes associated with clinical response. Additionally, in MSI-H uterine endometrial cancer patients, the length of time between the prior chemotherapy and the initiation of immunotherapy was negatively correlated with T cell reinvigoration post immunotherapy and clinical response. This suggests the importance of optimize therapeutic timing to maximize the therapeutic efficacy when combining immunotherapy and chemotherapy.ConclusionsCollectively, our immune profiling revealed the distinct immune signatures associated with clinical response to PD-1 blockade in gynecological cancers. Our results also suggest that TMBhi inflamed versus TMBlo cold tumor microenvironment, and timing of chemo/immunotherapy could impact differentiation and functions of T cells.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 and 17–182.

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