Open AccessEZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer
Author(s) -
Katherine L. Morel,
Anjali V. Sheahan,
Deborah L. Burkhart,
Sylvan C. Baca,
Nadia Boufaied,
Yin Liu,
Xintao Qiu,
Israel Cañadas,
Kevin Roehle,
Max Heckler,
Carla Calagua,
Huihui Ye,
Constantia Pantelidou,
Phillip M. Galbo,
Sukanya Panja,
Antonina Mitrofanova,
Scott Wilkinson,
Nichelle C. Whitlock,
Shana Y. Trostel,
Anis Hamid,
Adam S. Kibel,
David A. Barbie,
Atish D. Choudhury,
Mark M. Pomerantz,
Christopher J. Sweeney,
Henry W. Long,
David J. Einstein,
Geoffrey I. Shapiro,
Stephanie K. Dougan,
Adam G. Sowalsky,
Housheng Hansen He,
Matthew L. Freedman,
Steven P. Balk,
Massimo Loda,
David P. Labbé,
Brian M. Olson,
Leigh Ellis
Publication year - 2021
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-021-00185-w
Subject(s) - stimulator of interferon genes , prostate cancer , cancer research , ezh2 , interferon , blockade , immune checkpoint , cancer , cd8 , chemokine , medicine , immunology , immunotherapy , biology , immune system , innate immune system , receptor , gene expression , gene , biochemistry
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.