Abstract B006: Targeting EZH2 increases therapeutic efficacy of PD-1 blockade in models of prostate cancer

Prostate cancers are considered immunologically ‘cold’ tumors as they have demonstrated poor response to check-point inhibitor therapy (CPI). Recently, enrichment of interferon response genes suggests a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models increases expression of double-strand RNA (dsRNA), that is associated with upregulation of genes connected with antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response genes, including PD-L1. Likewise, application of a novel EZH2 derived gene signature and TMA analysis indicated an inverse correlation between tumor EZH2 activity/expression with, T-cell inflamed and IFN gene signatures, and PD-L1 expression in human prostate cancer samples. EZH2 inhibition combined with PD-1 CPI significantly enhances anti-tumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI. Citation Format: Anjali Sheahan, Katherine Morel, Deborah Burkhart, Sylvan Baca, David Labbe, Keven Roehle, Carla Calagua, Huihui Ye, Phillip Galbo, Sukanya Panja, Antonina Mitrofanova, Anis Hamid, Adam Kibel, Atish Choudhury, Mark Pomerantz, Matthew Freedman, Christopher Sweeney, Stephanie Dougan, Adam Sowalsky, Brian Olson, Massimo Loda, Leigh Ellis. Targeting EZH2 increases therapeutic efficacy of PD-1 blockade in models of prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B006. doi:10.1158/1535-7163.TARG-19-B006