Natural and anti-PD-L1 induced tumor immunity in a novel ovarian cancer mouse model for human mucin 1 (MUC1) (VAC3P.943)

MUC1 is a large cell surface glycoprotein overexpressed by almost all types of adenocarcinomas, including those originating in the ovaries. We recently generated a triple transgenic MKP mouse model that carry conditional Kras mutations, Pten deletion and express human MUC1 as self. Upon AdCre injection under the ovarian bursa, the MKP mice progress to endometrioid ovarian tumors. Using a freshly isolated, orthotopic ovarian tumor from a MKP mouse, we generated an ovarian cancer cell line MKP-T-2F8 (or simply 2F8) that triggers multiple MUC1 expressing intraperitoneal (IP) tumors. At baseline, the cells express low PD-L1 but expression increases after in vivo growth. Using the 2F8 transplantable tumor model, we tested in vivo the therapeutic effectiveness of anti-PD-L1 antibody (10F.9G2). MUC1.Tg or wild type mice were IP injected with 8x10E5 of 2F8 cells, followed by three doses of 200ug of anti-PD-L1 (or isotype control) antibody, administered IP every 2 weeks, starting 3 weeks post-tumor challenge. The anti-PD-L1 treated MUC1.Tg mice showed significantly increased survival (p= 0.02), with no evidence for peritoneal tumor. In contrast, wild type mice which grow 2F8 tumors and develop spontaneous anti-MUC1 antibodies in high titers, did not respond to anti-PD-L1 therapy. These results demonstrate that targeting PD-L1 is a viable therapeutic strategy in ovarian cancer; however, tumor-bearing hosts with Th2-driven immune imbalance may not benefit from PD-L1 blockade.