| Literature DB >> 33899001 |
Katherine L Morel1, Anjali V Sheahan1, Deborah L Burkhart1, Sylvan C Baca2, Nadia Boufaied3, Yin Liu4, Xintao Qiu2, Israel Cañadas5, Kevin Roehle6, Max Heckler6, Carla Calagua7, Huihui Ye8, Constantia Pantelidou2, Phillip Galbo9, Sukanya Panja10, Antonina Mitrofanova10,11, Scott Wilkinson12, Nichelle C Whitlock12, Shana Y Trostel12, Anis A Hamid2, Adam S Kibel13, David A Barbie2, Atish D Choudhury2, Mark M Pomerantz2, Christopher J Sweeney2, Henry W Long2, David J Einstein14, Geoffrey I Shapiro2, Stephanie K Dougan6, Adam G Sowalsky12, Housheng Hansen He4, Matthew L Freedman2, Steven P Balk14, Massimo Loda15, David P Labbé3,16, Brian M Olson17, Leigh Ellis18,19,20,21,22.
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.Entities:
Mesh：
Substances：
Year: 2021 PMID： 33899001 PMCID： PMC8061902 DOI： 10.1038/s43018-021-00185-w
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347