VEGF inhibits CD1d-mediated NKT cell activation

Purpose: Natural killer T (NKT) cells are important mediators of anti-tumor 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 vascular endothelial growth factor (VEGF). In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT cell-mediated anti-tumor responses. Experimental Design: 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 co-cultured 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. Results: 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 antigen presenting cells 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. Conclusions: 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 anti-angiogenic treatment has therapeutic potential in ovarian cancer.

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