MUC16 (CA125), a membrane spanning mucin, promotes proliferation and metastasis of ovarian cancer cells. Here, we demonstrate that MUC16 protects cancer cells from cytolysis by NK cells and macrophages. SCID mice implanted with MUC16-positive and MUC16-knockdown human ovarian tumors have a median survival of 75 and 181 days, respectively. Animals bearing MUC16-positive tumors developed ascites fluid and were moribund because of high tumor volume. In contrast, none of the mice with MUC16-knockdown tumors developed ascites. Decreased growth of MUC16-knockdown tumors correlated with increased cytolysis by murine splenocytes from naïve and anti-CD40 antibody treated mice. Murine NK cells showed a 2.5-fold higher preference for MUC16-knockdown cells. Unstimulated and LPS or IFN-γ-activated peritoneal macrophages from SCID mice also preferentially inhibited proliferation of MUC16-knockdown targets. Even in SCID/Beige mice, where cytolysis by resident NK cells is impaired, median survival MUC16-positive tumor-bearing animals was 75 days as compared to 189 days for animals with MUC16-knockdown tumors. All ten SCID/Beige mice with MUC16-knockdown tumors showed significant macrophage infiltration throughout the tumor nests and only two of the ten developed ascites. In contrast, 80% of SCID/Beige mice with MUC16-positive tumors had significant ascites and macrophages were predominantly found in the stroma. Finally, knockdown of MUC16 increased the susceptibility of cancer cells to natural cytotoxic responses of human NK cells, and increased their susceptibility to ADCC and lysis in the presence of immunocytokines. Therefore, strategies that decrease the expression of immunosuppressive MUC16 coupled with NK or macrophage-based immunotherapies should be investigated for the treatment of ovarian cancer.

Citation Format: Mildred Felder, Arvinder Kapur, Alexander L. Rakhmilevich, Xiaoyi Qu, Joseph Connor, Manish S. Patankar. MUC16 (CA125) knockdown as a potential strategy to decrease tumor growth [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1341.