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EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.
Morel, Katherine L; Sheahan, Anjali V; Burkhart, Deborah L; Baca, Sylvan C; Boufaied, Nadia; Liu, Yin; Qiu, Xintao; Cañadas, Israel; Roehle, Kevin; Heckler, Max; Calagua, Carla; Ye, Huihui; Pantelidou, Constantia; Galbo, Phillip; Panja, Sukanya; Mitrofanova, Antonina; Wilkinson, Scott; Whitlock, Nichelle C; Trostel, Shana Y; Hamid, Anis A; Kibel, Adam S; Barbie, David A; Choudhury, Atish D; Pomerantz, Mark M; Sweeney, Christopher J; Long, Henry W; Einstein, David J; Shapiro, Geoffrey I; Dougan, Stephanie K; Sowalsky, Adam G; He, Housheng Hansen; Freedman, Matthew L; Balk, Steven P; Loda, Massimo; Labbé, David P; Olson, Brian M; Ellis, Leigh.
Affiliation
  • Morel KL; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Sheahan AV; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Burkhart DL; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Baca SC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Boufaied N; Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada.
  • Liu Y; Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Center University Health Network, Toronto, Canada.
  • Qiu X; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Cañadas I; Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • Roehle K; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Heckler M; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Calagua C; Department of Medicine, Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Ye H; Department of Pathology, University of California at Los Angeles, Los Angeles, CA, USA.
  • Pantelidou C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Galbo P; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Panja S; Department of Health Informatics, Rutgers School of Health Professionals, Newark, NJ, USA.
  • Mitrofanova A; Department of Health Informatics, Rutgers School of Health Professionals, Newark, NJ, USA.
  • Wilkinson S; Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
  • Whitlock NC; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Trostel SY; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Hamid AA; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Kibel AS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Barbie DA; Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Choudhury AD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Pomerantz MM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Sweeney CJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Long HW; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Einstein DJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Shapiro GI; Hematology and Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Dougan SK; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Sowalsky AG; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • He HH; Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Freedman ML; Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Center University Health Network, Toronto, Canada.
  • Balk SP; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Loda M; Hematology and Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Labbé DP; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
  • Olson BM; Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada.
  • Ellis L; Division of Urology, Department of Surgery, McGill University, Montréal, Canada.
Nat Cancer ; 2(4): 444-456, 2021 04.
Article in En | MEDLINE | ID: mdl-33899001
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Programmed Cell Death 1 Receptor Type of study: Prognostic_studies Limits: Humans / Male Language: En Journal: Nat Cancer Year: 2021 Document type: Article Affiliation country: United States
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Programmed Cell Death 1 Receptor Type of study: Prognostic_studies Limits: Humans / Male Language: En Journal: Nat Cancer Year: 2021 Document type: Article Affiliation country: United States