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Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity

2018; Cell Press; Volume: 23; Issue: 11 Linguagem: Inglês

10.1016/j.celrep.2018.05.050

2639-1856

David Wang, Jason Quiros, Kelly Mahuron, Chien-Chun Steven Pai, Valeria Ranzani, Arabella Young, Stephanie Silveria, Tory Harwin, Arbi Abnousian, Massimiliano Pagani, Michael D. Rosenblum, Frédéric Van Gool, Lawrence Fong, Jeffrey A. Bluestone, Michel DuPage,

Cancer Immunotherapy and Biomarkers

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.