PD-L1 blockade and upregulation in an ovarian cancer treatment model (TUM2P.1017)

Abstract

Abstract Objective: We explored mechanisms of PD-L1 upregulation in ovarian cancer cells and tested in vivo the efficacy of intraperitoneal anti-PD-L1 therapy in two different ovarian cancer mouse models. Methods: We have derived several novel murine ovarian cancer cell lines from orthotopic ovarian tumors of triple transgenic mice. 129x SvJ and C57Bl/6 tumor-bearing mice were treated with 200 μg anti-PD-L1 antibody (or rat IgG as control) every two weeks for three doses. Immune gene profiling of splenocytes collected at necropsy was performed using 561 Nanostring probes. Results: Cell cycle analysis of in vitro cultured tumor cells demonstrates that PD-L1 expression increases preferentially on cells in G2/M cells. Exposure to cisplatin modifies PD-L1 levels, although the effect varies according to tumors’ baseline susceptibility. In vivo, we observed murine PD-L1 upregulation on ascites resident tumor cells, an effect reproduced ex vivo upon exposure of tumor cells to ascites fluid. PD-L1 blockade triggers increase in survival in both preclinical models with immune gene signatures pointing to cytotoxic anti-tumor immune response. Conclusion: PD-L1 expression increases in response to inflammatory stimuli from cell-free ascites and shows preference for dividing cells. PD-L1 upregulation varies according to tumor cells’ susceptibility to cisplatin. PD-L1 blockade increases systemic T cell responses and intratumoral T cell accumulation suggesting therapeutic potential in ovarian cancer.