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

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 Galbo; Sukanya Panja; Antonina Mitrofanova; Scott Wilkinson; Nichelle C Whitlock; Shana Y Trostel; Anis A 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

doi:10.1038/s43018-021-00185-w

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. doi: 10.1038/s43018-021-00185-w. Epub 2021 Mar 22.

Authors

Katherine L Morel^#¹, Anjali V Sheahan^#¹, 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 Mitrofanova^{10

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 Labbé^{3

16}, Brian M Olson¹⁷, Leigh Ellis^{18

19

20

21

22}

Affiliations

¹ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada.
⁴ Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Center University Health Network, Toronto, Canada.
⁵ Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁶ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Medicine, Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, University of California at Los Angeles, Los Angeles, CA, USA.
⁹ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
¹⁰ Department of Health Informatics, Rutgers School of Health Professionals, Newark, NJ, USA.
¹¹ Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
¹² Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹³ Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Hematology and Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁶ Division of Urology, Department of Surgery, McGill University, Montréal, Canada.
¹⁷ Departments of Hematology and Medical Oncology and Urology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁸ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁹ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
²⁰ Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
²¹ Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
²² Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Enhancer of Zeste Homolog 2 Protein / genetics
Humans
Interferons / pharmacology
Male
Programmed Cell Death 1 Receptor*
Prostatic Neoplasms* / drug therapy
RNA, Double-Stranded

Substances

Programmed Cell Death 1 Receptor
RNA, Double-Stranded
Interferons
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding