Abstract AP31: TARGETING PD–L1/PD1 PATHWAY THROUGH BET PROTEIN INHIBITION IN EPITHELIAL OVARIAN CANCER

Abstract

Abstract BACKGROUND: Expression of programmed death ligand 1 (PD-L1) is up-regulated in many cancers and has been found to suppress antitumor immunity through binding to its receptor programmed death 1 (PD-1). Blockade of PD-1/PD-L1 signaling axis enhances antitumor immunity in many cancers including epithelial ovarian cancer (EOC). Despite the importance of PD-L1 in tumor immunity, the epigenetic regulation of PD-L1 expression remains poorly understood. AIMS: To determine the roles of epigenetic components in regulating PD-L1 gene expression and modulating antitumor immunity. METHODS: Toward this goal, I screened a small molecule library of epigenetic inhibitors and examined their inhibition on PD-L1 expression in EOC cells to identify the positive hits. To further confirm PD-L1 inhibition in vivo, C57BL/6 mice are injected with luciferase expressing mouse ovarian cancer ID8 cells and treated with or without epigenetic inhibitors, PD-L1 expression in both tumor cells and immune cells are examined, tumor growth and survival are also monitored. RESULTS: BET inhibitors suppresses both constitutive and IFNγ induced PD-L1 expression in EOC cells through targeting BRD4. Further ChIP-seq and ChIP assay demonstrate that BRD4 directly binds to PD-L1 gene promoter and regulated its transcription. BET inhibitor JQ1 suppresses PD-L1 expression in both tumor cells and immune cells including dendritic cells and macrophages in mice bearing ID8 mouse ovarian cancer cells. Moreover, the BET inhibitor suppresses the tumor growth and improves the survival of EOC bearing mice through activating antitumor T cells. CONCLUSION: Taken together, we demonstrated that BRD4 can directly regulate PD-L1 expression in EOC cells by binding to the promoter of PD-L1 encoding gene, suppressing PD-L1 expression with BET inhibitors blocks PD1/PD-L1 signaling and enhances antitumor immunity in vivo. These findings indicate that pharmacological inhibition of BET proteins represent a new therapeutic strategy for EOC by targeting PD-L1 expression. Citation Format: Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R. Rutkowski, Benjamin G. Bitler, Michael J. Allegrezza, Yuhki Yokoyama, James E. Bradner, Jose R. Conejo-Garcia, Rugang Zhang. TARGETING PD–L1/PD1 PATHWAY THROUGH BET PROTEIN INHIBITION IN EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP31.