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VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells.

ABSTRACT: Natural killer T (NKT) cells are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which inhibits NKT-cell activation. Ovarian cancers also secrete high levels of VEGF. In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT-cell-mediated antitumor responses.To investigate the effects of VEGF on CD1d-mediated NKT-cell activation, a conditioned media model was established, wherein the supernatants from ovarian cancer cell lines (OV-CAR-3 and SK-OV-3) were used to treat CD1d-expressing antigen-presenting cells (APC) and cocultured with NKT hybridomas. Ovarian cancer-associated VEGF was inhibited by treatment with bevacizumab and genistein; conditioned medium was collected, and CD1d-mediated NKT-cell responses were assayed by ELISA.Ovarian cancer tissue and ascites contain lymphocytic infiltrates, suggesting that immune cells traffic to tumors, but are then inhibited by immunosuppressive molecules within the tumor microenvironment. OV-CAR-3 and SK-OV-3 cell lines produce high levels of VEGF and GD3. Pretreatment of APCs with ascites or conditioned medium from OV-CAR-3 and SK-OV-3 blocked CD1d-mediated NKT-cell activation. Inhibition of VEGF resulted in a concomitant reduction in GD3 levels and restoration of NKT-cell responses.We found that VEGF inhibition restores NKT-cell function in an in vitro ovarian cancer model. These studies suggest that the combination of immune modulation with antiangiogenic treatment has therapeutic potential in ovarian cancer. Clin Cancer Res; 22(16); 4249-58. ©2016 AACR.

SUBMITTER: Tiper IV

PROVIDER: S-EPMC4987212 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells.

Tiper Irina V IV Temkin Sarah M SM Spiegel Sarah S Goldblum Simeon E SE Giuntoli Robert L RL Oelke Mathias M Schneck Jonathan P JP Webb Tonya J TJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20160413 16

<h4>Purpose</h4>Natural killer T (NKT) cells are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which inhibits NKT-cell activation. Ovarian cancers also secrete high levels of VEGF. In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT-cell-mediated antitumor responses.<h4>Experimental design</h4>To investigate the effects of VEGF on CD1d-mediated NKT-cell activation, a co ...[more]

PMID: 27076627

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Project description:The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BL/6, B6.129S7-Rag1tm1Mom/J, and B6.129P2(SJL)-Myd88tm1.1Defr/J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TMβ1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro. We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1tm1Mom/J mice compared to immunocompetent C57BL/6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BL/6 mice (p = 0.004) and in B6.129S7-Rag1tm1Mom/J mice (p = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines (p ≤ 0.02) and monocytic MDSC (p ≤ 0.01). Selective depletion of MDSC by anti-GR1 improved survival, certainly in comparison to mice treated with anti-CSF1 (p = 0.01-median survival 91 vs. 67.5 days). B6.129P2(SJL)-Myd88tm1.1Defr/J mice displayed to a longer median survival compared to C57BL/6 mice (90 vs. 76 days). MDSC activated by ID8-fLuc conditioned medium or ascites of tumor-bearing mice showed T cell suppressive functions in vitro. Based on these findings, we conclude that the adaptive immune system does not efficiently control tumor growth in the ID8-fLuc model. In addition, we discovered a prominent role for MDSC as the driver of immunosuppression in the ID8-fLuc ovarian cancer mouse model.

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VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells.

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VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells.

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