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

TitleEZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsMorel 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
JournalNat Cancer
Volume2
Issue4
Pagination444-456
Date Published2021 Apr
ISSN2662-1347
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.

DOI10.1038/s43018-021-00185-w
Alternate JournalNat Cancer
PubMed ID33899001
PubMed Central IDPMC8061902
Grant ListR21 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.

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