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

doi:10.1016/j.celrep.2018.05.050

Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity

Cell Rep. 2018 Jun 12;23(11):3262-3274. doi: 10.1016/j.celrep.2018.05.050.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Istituto Nazionale Genetica Molecolare (INGM) "Romeo ed Enrica Invernizzi," Milan 20122, Italy.
⁶ Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁸ 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.
⁹ Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ 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.
¹¹ Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. Electronic address: jeff.bluestone@ucsf.edu.
¹² 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. Electronic address: dupage@berkeley.edu.

Abstract

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.

Publication types

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

MeSH terms

Animals
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein / deficiency
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism*
Forkhead Transcription Factors / metabolism
Humans
Interferon-gamma / metabolism
Lymphocytes, Tumor-Infiltrating / cytology
Lymphocytes, Tumor-Infiltrating / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms / immunology
Neoplasms / pathology
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism*
Tumor Microenvironment
Tumor Necrosis Factor-alpha / metabolism

Substances

Forkhead Transcription Factors
Foxp3 protein, mouse
Tumor Necrosis Factor-alpha
Interferon-gamma
Enhancer of Zeste Homolog 2 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding