Cell surface MUC16: Metastasis, immune evasion, and the promise of immunocytokine therapies in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most deadly of gynecological cancers and is the seventh-leading cause of cancer deaths in women. This tumor is highly metastatic and tumor cell aggregates are found throughout the peritoneal cavity. The suppressed immune system of EOC patients is also a factor in this deadly disease. EOC tumor cells highly express a large molecular weight protein called MUC 16 (known clinically as CAl25). This mucin is over 3 million Da and may extend over 1 micron from the cell surface. MUC16, as part of the mucin family, has anti-adhesive and adhesive characteristics. The work presented in this dissertation will show that MUC16 acts as an adhesive molecule and facilitates metastasis of ovarian tumor cells. We will also demonstrate that MUC16, because of its anti-adhesive function, also helps the ovarian tumors to evade natural killer (NK) cell mediated cytotoxic responses. Finally, our results indicate that the immune evasion due to MUC16 expression on the surface of ovarian cancer cells can be successfully circumvented when cancer cells are treated with immunocytokines, anti-tumor antibodies fused to cytokine molecules. In this context we will also demonstrate that immunocytokines are highly effective in bridging cancer cells and effector cells via a novel CD25-mediated mechanism.