TY - JOUR
T1 - EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer
AU - Morel, Katherine L.
AU - Sheahan, Anjali V.
AU - Burkhart, Deborah L.
AU - Baca, Sylvan C.
AU - Boufaied, Nadia
AU - Liu, Yin
AU - Qiu, Xintao
AU - Cañadas, Israel
AU - Roehle, Kevin
AU - Heckler, Max
AU - Calagua, Carla
AU - Ye, Huihui
AU - Pantelidou, Constantia
AU - Galbo, Phillip
AU - Panja, Sukanya
AU - Mitrofanova, Antonina
AU - Wilkinson, Scott
AU - Whitlock, Nichelle C.
AU - Trostel, Shana Y.
AU - Hamid, Anis A.
AU - Kibel, Adam S.
AU - Barbie, David A.
AU - Choudhury, Atish D.
AU - Pomerantz, Mark M.
AU - Sweeney, Christopher J.
AU - Long, Henry W.
AU - Einstein, David J.
AU - Shapiro, Geoffrey I.
AU - Dougan, Stephanie K.
AU - Sowalsky, Adam G.
AU - He, Housheng Hansen
AU - Freedman, Matthew L.
AU - Balk, Steven P.
AU - Loda, Massimo
AU - Labbé, David P.
AU - Olson, Brian M.
AU - Ellis, Leigh
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - CD8-Positive T-Lymphocytes
KW - Enhancer of Zeste Homolog 2 Protein/genetics
KW - Humans
KW - Interferons/pharmacology
KW - Male
KW - Programmed Cell Death 1 Receptor
KW - Prostatic Neoplasms/drug therapy
KW - RNA, Double-Stranded
UR - http://www.scopus.com/inward/record.url?scp=85103203231&partnerID=8YFLogxK
U2 - 10.1038/s43018-021-00185-w
DO - 10.1038/s43018-021-00185-w
M3 - Article
C2 - 33899001
AN - SCOPUS:85103203231
SN - 2662-1347
VL - 2
SP - 444
EP - 456
JO - Nature Cancer
JF - Nature Cancer
IS - 4
ER -
