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Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity.

  • Author(s): Wang, David
  • Quiros, Jason
  • Mahuron, Kelly
  • Pai, Chien-Chun
  • Ranzani, Valeria
  • Young, Arabella
  • Silveria, Stephanie
  • Harwin, Tory
  • Abnousian, Arbi
  • Pagani, Massimiliano
  • Rosenblum, Michael D
  • Van Gool, Frederic
  • Fong, Lawrence
  • Bluestone, Jeffrey A
  • DuPage, Michel
  • et al.

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.

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