Ovarian cancer (OC) has the highest mortality rate of all gynecological malignancies. While clinical outcomes have been reported to be independent of typical features such as stage, grade, or response to therapy, there is a positive correlation between OC survival and immune cell infiltration into the tumor microenvironment. Given that immune-based therapies have only had modest success, there is a critical need to identify the mechanisms by which OC evades cancer immune surveillance. Studies in our lab are focused on natural killer T (NKT) cells, which recognize lipid antigens presented by CD1d molecules and are potent anti-tumor effector cells. We have found NKT cells present within the OC microenvironment and can directly kill OC cell lines; however, OC utilizes multiple mechanisms to inhibit NKT cell activation. We previously reported that OC cells shed the ganglioside GD3, which blocks NKT cell activation. OC cells also produce high levels of vascular endothelial growth factor (VEGF), which directly suppresses NKT cell activation and indirectly mitigates their function by reducing CD1d-mediated antigen presentation. Moreover, VEGF potentiates GD3-mediated immune suppression. Importantly, in the absence of these immunosuppressive factors, OC cell lines directly induce NKT cell activation. These data strongly suggest that blocking immunosuppressive factors by OC will enhance cancer immune surveillance. Therefore, the goal of the project is to determine the effectiveness of VEGF inhibitors, such as those derived from natural compounds in green tea, licorice, and ginseng, in enhancing NKT cell-mediated cytotoxicity. To test these therapeutics, we will perform time course assays and dose-response curves using ID8-GLuc, a murine OC cell line and assess cellular viability, proliferative capacity, and VEGF secretion. Once we have optimized our treatment conditions, we will investigate whether VEGF inhibition sensitizes OC to NKT cell-mediated killing. Collectively, these studies have the potential to increase our understanding of novel therapeutic strategies that can be used restore anti-tumor immunity and result in improved outcomes for ovarian cancer patients.