EZH2 as an Actionable Therapeutic Target to Enhance Anti-Tumor Immune Response In Prostate Cancer

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.

Learning Objectives:

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.