Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity
David Wang,
Jason Quiros,
Kelly Mahuron,
Chien-Chun Pai,
Valeria Ranzani,
Arabella Young,
Stephanie Silveria,
Tory Harwin,
Arbi Abnousian,
Massimiliano Pagani,
Michael D. Rosenblum,
Frederic Van Gool,
Lawrence Fong,
Jeffrey A. Bluestone,
Michel DuPage
Affiliations
David Wang
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Pediatric Hematology and Oncology, University of California, San Francisco Benioff Children’s Hospital, San Francisco, CA 94158, USA
Jason Quiros
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
Kelly Mahuron
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Chien-Chun Pai
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
Valeria Ranzani
Istituto Nazionale Genetica Molecolare (INGM) “Romeo ed Enrica Invernizzi,” Milan 20122, Italy
Arabella Young
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
Stephanie Silveria
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
Tory Harwin
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Arbi Abnousian
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Massimiliano Pagani
Istituto Nazionale Genetica Molecolare (INGM) “Romeo ed Enrica Invernizzi,” Milan 20122, Italy; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano 20129, Italy
Michael D. Rosenblum
Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
Frederic Van Gool
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
Lawrence Fong
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
Jeffrey A. Bluestone
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Corresponding author
Michel DuPage
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Corresponding author
Summary: Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity. : EZH2 plays an intrinsic role in neoplastic cells as an oncogene, prompting the development of EZH2 inhibitors for cancer therapy. Wang et al. show that disrupting EZH2 function also has immunomodulatory activities and, when blocked in Tregs, promotes potent cancer immunity.
