EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer

Ellis and colleagues show that combination of EZH2 inhibition and anti-PD-1 can increase antitumor immune responses in typically 'immune cold' prostate cancer, by increasing EZH2-regulated dsRNA-STING-ISG response signaling. Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA-STING-ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8(+) T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.

Automated summary

Combination of EZH2 inhibition and anti-PD-1 has been shown to enhance antitumor immune responses in prostate cancer by activating the dsRNA-STING-ISG stress response signaling; EZH2 inhibition upregulates genes involved in antigen presentation and interferon response, suggesting it as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.