Title | EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Morel KL, Sheahan AV, Burkhart DL, Baca SC, Boufaied N, Liu Y, Qiu X, Cañadas I, Roehle K, Heckler M, Calagua C, Ye H, Pantelidou C, Galbo P, Panja S, Mitrofanova A, Wilkinson S, Whitlock NC, Trostel SY, Hamid AA, Kibel AS, Barbie DA, Choudhury AD, Pomerantz MM, Sweeney CJ, Long HW, Einstein DJ, Shapiro GI, Dougan SK, Sowalsky AG, He HHansen, Freedman ML, Balk SP, Loda M, Labbé DP, Olson BM, Ellis L |
Journal | Nat Cancer |
Volume | 2 |
Issue | 4 |
Pagination | 444-456 |
Date Published | 2021 Apr |
ISSN | 2662-1347 |
Abstract | 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. |
DOI | 10.1038/s43018-021-00185-w |
Alternate Journal | Nat Cancer |
PubMed ID | 33899001 |
PubMed Central ID | PMC8061902 |
Grant List | R21 CA205627 / CA / NCI NIH HHS / United States Z99 CA999999 / ImNIH / Intramural NIH HHS / United States ZIA BC011679 / ImNIH / Intramural NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.