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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 HH , Freedman ML , Balk SP , Loda M , Labbé DP , Olson BM , Ellis L
EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer
Nat Cancer. 2021 Apr;2(4) :444-456
PMID: 33899001    PMCID: PMC8061902   
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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.
Notes
2662-1347 Morel, Katherine L Orcid: 0000-0002-7968-4032 Sheahan, Anjali V Burkhart, Deborah L Baca, Sylvan C Boufaied, Nadia Liu, Yin Qiu, Xintao Orcid: 0000-0002-8560-7017 Cañadas, Israel Roehle, Kevin Heckler, Max Calagua, Carla Ye, Huihui Pantelidou, Constantia Orcid: 0000-0003-2750-9352 Galbo, Phillip Orcid: 0000-0002-5391-598x Panja, Sukanya Mitrofanova, Antonina Orcid: 0000-0003-0671-6512 Wilkinson, Scott Orcid: 0000-0002-2613-8425 Whitlock, Nichelle C Trostel, Shana Y Hamid, Anis A Kibel, Adam S Barbie, David A Orcid: 0000-0002-5422-4275 Choudhury, Atish D Pomerantz, Mark M Sweeney, Christopher J Long, Henry W Orcid: 0000-0001-6849-6629 Einstein, David J Shapiro, Geoffrey I Dougan, Stephanie K Sowalsky, Adam G Orcid: 0000-0003-2760-1853 He, Housheng Hansen Freedman, Matthew L Orcid: 0000-0002-0151-1238 Balk, Steven P Orcid: 0000-0002-4546-7371 Loda, Massimo Labbé, David P Orcid: 0000-0001-8864-8765 Olson, Brian M Ellis, Leigh Orcid: 0000-0003-4739-5049 R21 CA205627/CA/NCI NIH HHS/United States Z99 CA999999/ImNIH/Intramural NIH HHS/United States ZIA BC011679/ImNIH/Intramural NIH HHS/United States Journal Article Nat Cancer. 2021 Apr;2(4):444-456. doi: 10.1038/s43018-021-00185-w. Epub 2021 Mar 22.