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

• Type of Material: Article
• Authors: Katherine L. Morel, Dana Farber Cancer Institute; Anjali V. Sheahan, Dana Farber Cancer Institute; Deborah L. Burkhart, Dana Farber Cancer Institute; Sylvan C. Baca, Dana Farber Cancer Institute; Nadia Boufaied, McGill University; Yin Liu, University of Toronto; Xintao Qiu, Dana Farber Cancer Institute; Israel Canadas, Fox Chase Cancer Center; Kevin Roehle, Dana Farber Cancer Institute; Max Heckler, Dana Farber Cancer Institute; Carla Calagua, Harvard Medical School; Huihui Ye, University of California Los Angeles; Constantia Pantelidou, Dana Farber Cancer Institute; Philip Galbo, Albert Einstein College of Medicine; Sukanya Panja, Rutgers State University; Antonina Mitrofanova, Rutgers State University; Scott Wilkinson, NCI; Nichelle C. Whitlock, NCI; Shana Y. Trostel, NCI; Anis A. Hamid, Dana Farber Cancer Institute; Adam S. Kibel, Harvard Medical School; David A. Barbie, Dana Farber Cancer Institute; Atish D. Choudhury, Dana Farber Cancer Institute; Mark M. Pomerantz, Dana Farber Cancer Institute; Christopher J. Sweeney, Dana Farber Cancer Institute; Henry W. Long, Dana Farber Cancer Institute; David J. Einstein, Beth Israel Deaconess Medical Center; Geoffrey I. Shapiro, Dana Farber Cancer Institute; Stephanie K. Dougan, Dana Farber Cancer Institute; Adam G. Sowalsky, NCI; Housheng Hansen He, University of Toronto; Matthew L. Freedman, Dana Farber Cancer Institute; Stephanie K. Balk, Beth Israel Deaconess Medical Center; Massimo Loda, Weill Cornell Medical College; David P. Labbe, McGill University; Brian Olson, Emory University; Leigh Ellis, Dana Farber Cancer Institute
• Language: English
• Date: 2021-03-22
• Publisher: Nature Portfolio
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Springer Nature Limited.
• Final Published Version (URL): http://dx.doi.org/10.1038/s43018-021-00185-w
• Title of Journal or Parent Work: Nature Cancer
• Volume: 2
• Issue: 4
• Start Page: 444
• End Page: +
• Grant/Funding Information: Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI; to A.G.S.).; We thank Epizyme Pharmaceuticals for supplying EPZ0011989.; The present study was supported by Dana-Farber Cancer Institute Faculty Start-Up Funds (to L.E.); B.M.O was supported by Emory University Faculty Start-Up funds.; Prostate Cancer Foundation Young Investigator Award (to L.E., D.P.L., S.W. and A.G.S.); This research project was supported in part by the Emory University School of Medicine Flow Cytometry Core (to B.M.O.).; D.P.L. is a Lewis Katz recipient of a Scholarship for the Next Generation of Scientists from the Cancer Research Society, and is also a Research Scholar, Junior 1 of the Fonds de la recherche du Québec-Santé.
• Keywords: Inactivation; Methylation; Science & Technology; Oncology; Expression; Cells; Mouse models; Chemokines; Life Sciences & Biomedicine; Protein EZH2; Polycomb; Plasticity; Generation
• Research Categories: Biology, Cell; Health Sciences, Oncology; Biophysics, Medical; Health Sciences, Immunology

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.