Prostate cancers are considered immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon stimulated genes (ISGs) predicts 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 ISGs. Here, we demonstrate that EZH2 inhibition in prostate cancer models activates a dsRNA-STING-ISG stress response upregulating genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1 that is dependent on STING activation. EZH2 inhibition significantly increased intratumoral trafficking of activated CD8+ T-cells and increased M1 tumor associated macrophages (TAMs), overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.
1. Identify epigenetic mechanisms important for prostate cancer immune evasion.
2. Define EZH2 inhibition has a rational approach to reverse prostate cancer resistance to check-point inhibitors.