Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells

Horikawa, Naoki; Abiko, Kaoru; Matsumura, Noriomi; Hamanishi, Junzo; Baba, Tsukasa; Yamaguchi, Ken; Yoshioka, Yumiko; Koshiyama, Masafumi; Konishi, Ikuo

doi:10.1158/1078-0432.ccr-16-0387

Cited by 216 publications

(181 citation statements)

References 51 publications

(62 reference statements)

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“…26 Although the precise molecular mechanism for the differentiation of MDSCs is yet to be defined, the expansion and accumulation of these cells are known to be mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial cell growth (VEGF) and IL-4. 27,28 In this study, we showed that the frequency of which is in line with a prior report. 10 It is known that HCV infection can lead to inflammation in the liver and the secretion of inflammatory cytokines, which may result in damage to hepatocytes and the release of ALT in the blood.…”

Section: Mdscs From Chc Patients Suppress Autologous T-cell Proliferasupporting

confidence: 93%

“…For human MDSCs, the M‐MDSCs subset mainly express CD14, whereas the G‐MDSCs do not express CD14 . Although the precise molecular mechanism for the differentiation of MDSCs is yet to be defined, the expansion and accumulation of these cells are known to be mediated by granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), vascular endothelial cell growth (VEGF) and IL‐4 . In this study, we showed that the frequency of G‐MDSCs was positively correlated with the concentration of serum HCVc in patients with CHC, suggesting that circulating HCVc plays a role in the development of G‐MDSCs and may mediate immune suppression.…”

Section: Discussionmentioning

confidence: 81%

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Polarization of granulocytic myeloid‐derived suppressor cells by hepatitis C core protein is mediated via IL‐10/STAT3 signalling

Wang

Yü

et al. 2018

Journal of Viral Hepatitis

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Summary Myeloid‐derived suppressor cells (MDSCs) have been described as suppressors of T‐cell function in many malignancies. Impaired T‐cell responses have been observed in patients with chronic hepatitis C virus infection (CHC), which is reportedly associated with the establishment of persistent HCV infection. Therefore, we hypothesized that MDSCs also play a role in chronic HCV infection. MDSCs in the peripheral blood of 206 patients with CHC and 20 healthy donors were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) of healthy donors cultured with hepatitis C virus core protein (HCVc) were stimulated with or without interleukin 10 (IL‐10). Compared to healthy donors and certain CHC patients with sustained viral response (SVR), CHC patients without SVR presented with a dramatic elevation of G‐MDSCs with the HLA‐DR−/lowCD33+CD14−CD11b+ phenotype in peripheral blood. The frequency of G‐MDSCs in CHC patients was positively correlated with serum HCVc, and G‐MDSCs were induced from healthy PBMCs by adding exogenous HCVc. Furthermore, we revealed a potential mechanism by which HCVc mediates G‐MDSC polarization; activation of ERK1/2 resulting in IL‐10 production and IL‐10‐activated STAT3 signalling. Finally, we confirmed that HCVc‐induced G‐MDSCs suppress the proliferation and production of IFN‐γ in autologous T‐cells. We also found that the frequency of G‐MDSCs in serum was associated with CHC prognosis. HCVc maintains immunosuppression by promoting IL‐10/STAT3‐dependent differentiation of G‐MDSCs from PBMCs, resulting in the impaired functioning of T‐cells. G‐MDSCs may thus be a promising biomarker for predicting prognosis of CHC patients.

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Section: Mdscs From Chc Patients Suppress Autologous T-cell Proliferasupporting

confidence: 93%

Section: Discussionmentioning

confidence: 81%

Polarization of granulocytic myeloid‐derived suppressor cells by hepatitis C core protein is mediated via IL‐10/STAT3 signalling

Wang

Yü

et al. 2018

Journal of Viral Hepatitis

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“…Horikawa et al have shown recently that the VEGF-A/VEGFR2 pathway increases intratumoral MDSCs and promotes tumor progression in a mouse ovarian cancer model. They also showed that VEGF expression correlated with MDSCs infiltration in human samples from the peritoneum of ovarian cancer patients with disseminated disease (67). Besides these effects on immunoregulatory cells, a direct inhibition of conventional T cells by VEGF-A has been reported (68).…”

Section: Hypoxia In Rt-treated Tumors and Immune Regulation By Hif-1αmentioning

confidence: 97%

Barriers to Radiation-Induced In Situ Tumor Vaccination

et al. 2017

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The immunostimulatory properties of radiation therapy (RT) have recently generated widespread interest due to preclinical and clinical evidence that tumor-localized RT can sometimes induce antitumor immune responses mediating regression of non-irradiated metastases (abscopal effect). The ability of RT to activate antitumor T cells explains the synergy of RT with immune checkpoint inhibitors, which has been well documented in mouse tumor models and is supported by observations of more frequent abscopal responses in patients refractory to immunotherapy who receive RT during immunotherapy. However, abscopal responses following RT remain relatively rare in the clinic, and antitumor immune responses are not effectively induced by RT against poorly immunogenic mouse tumors. This suggests that in order to improve the pro-immunogenic effects of RT, it is necessary to identify and overcome the barriers that pre-exist and/or are induced by RT in the tumor microenvironment. On the one hand, RT induces an immunogenic death of cancer cells associated with release of powerful danger signals that are essential to recruit and activate dendritic cells (DCs) and initiate antitumor immune responses. On the other hand, RT can promote the generation of immunosuppressive mediators that hinder DCs activation and impair the function of effector T cells. In this review, we discuss current evidence that several inhibitory pathways are induced and modulated in irradiated tumors. In particular, we will focus on factors that regulate and limit radiation-induced immunogenicity and emphasize current research on actionable targets that could increase the effectiveness of radiation-induced in situ tumor vaccination.

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“…The VEGF-driven accumulation of CD33 + myeloid-derived suppressor cells (MDSCs), particularly in the omentum, also correlates with a failure to accumulate CD8 + TILs, the suppression of T cell function and a poor prognosis in ovarian cancer patients [91]. Similarly, CD33 + MDSCs that accumulate in peritoneal ascites fluid of ovarian cancer patients express nitric oxide synthase-2 (NOS2) and produce NO [92], which promotes the differentiation of Th17 cells and impairs the function of Th1 and CD8 + T cells.…”

Section: Peritoneal Tumor Metastasis In the Omentummentioning

confidence: 99%

Immunological Functions of the Omentum

Meza-Pérez

Randall

2017

Trends in Immunology

222

176

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The omentum is a visceral adipose tissue with unique immune functions. Although it is primarily an adipose tissue, the omentum also contains lymphoid aggregates, called milky spots (MS), that contribute to peritoneal immunity by collecting antigens, particulates and pathogens from the peritoneal cavity and, depending on the stimuli, promoting a variety of immune responses, including inflammation, tolerance or even fibrosis. Reciprocal interactions between cells in the MS and adipocytes regulate their immune and metabolic functions. Importantly, the omentum collects metastasizing tumor cells and supports tumor growth by immunological and metabolic mechanisms. Here we summarize our current knowledge about the development, organization and function of the omentum in peritoneal immunity.

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Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells

Abstract: VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis. Clin Cancer Res; 23(2); 587-99. ©2016 AACR.

Cited by 216 publications

References 51 publications

Polarization of granulocytic myeloid‐derived suppressor cells by hepatitis C core protein is mediated via IL‐10/STAT3 signalling

Polarization of granulocytic myeloid‐derived suppressor cells by hepatitis C core protein is mediated via IL‐10/STAT3 signalling

Barriers to Radiation-Induced In Situ Tumor Vaccination

Immunological Functions of the Omentum

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