Targeting the VEGF/GD3 immunosuppressive axis in ovarian cancer

Abstract

Abstract Ovarian cancer is the fifth leading cause of cancer deaths among women, thereby accounting for more deaths than any other cancer of the female reproductive system. It is known that 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. Moreover, vascular endothelial growth factor (VEGF) expression is inversely correlated with survival in ovarian cancer patients. Since avoiding detection by the host’s immune system is crucial for the growth and metastasis of cancer, we investigated the effects of ovarian cancer-associated VEGF on CD1d-mediated antigen presentation to natural killer T (NKT) cells. Pretreatment of antigen presenting cells with ascites or conditioned medium from OV-CAR-3 and SK-OV-3 ovarian cancer cell lines suppressed CD1d-mediated NKT cell activation. Ovarian cancer-associated ascites and conditioned medium from ovarian cancer cell lines contain high levels of VEGF and the ganglioside GD3. Importantly, inhibiting VEGF production by ovarian cancer cell lines led to a reduction in GD3 expression and restored NKT cell activation. To elucidate the mechanisms by which VEGF induces GD3 shedding by ovarian cancer cells, we are examining signaling through the VEGF-receptor, assessing its impact in vivo using the ID8-VEGF ovarian cancer mouse model, as well as measuring levels in human blood and ascites. Collectively, these studies identify novel mechanisms through which VEGF impairs anti-tumor immune responses and thus have the potential to enhance therapeutic strategies for the treatment of ovarian cancer.