Prostate cancers are considered immunologically cold tumors as they demonstrate poor response to check-point inhibitor therapy (CPI). Enrichment of interferon gamma (IFNγ) response genes, critical for innate and adaptive immune response to viral infections, have been demonstrated to indicate a positive response to CPI. Tumor IFNγ signaling acts as both an activator and inhibitor of effector T-cell response/trafficking via regulation of Th-1 chemokines (CXCL9/10), and immune checkpoints (PD-L1 and PD-1). Enhancer of zeste homolog-2 (EZH2) is a histone methyltransferase that mediates gene repression, is commonly over-expressed in prostate cancer and is known to negative regulate IFN response genes. With this, we hypothesized that inhibition of EZH2 would induce IFN gene response and potentiate prostate tumor response to CPI. EZH2 inhibition of 3D prostate tumor organoids significantly induced double-strand RNA and PD-L1 expression, and IFN response gene signatures. Generation of a novel EZH2 repression signature (EZH2_RS) was used to segregate prostate cancer patients, from three independent clinical cohorts, based on EZH2 activity. Correlation analysis confirmed that tumors with low EZH2 function had increased enrichment of IFNγ response and Th1 immune cell infiltration gene signatures, and PD-L1 gene expression. By employing a mixed lymphocytic reaction assay, we demonstrated that EZH2 inhibition significantly repressed splenocyte-mediated cytotoxic tumor elimination, which is rescued upon CPI. In vivo, the combination of EZH2 inhibition and CPI significantly slowed prostate tumor growth compared to control and single therapy arms. Collectively, our findings indicate EZH2 mediates prostate cancer immune evasion and its subsequent inhibition enables CPI response. This data provides strong rationale for further clinical development of this combination strategy for the treatment of prostate cancer.
17 Mar 2019 - 20 Mar 2019