期刊
CELL REPORTS
卷 23, 期 11, 页码 3262-3274出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.05.050
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资金
- NIH [R01 AI046643, UM1 AI-12-059]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG2013-ID14596]
- Parker Institute for Cancer Immunotherapy
- UCSF Cancer Immunotherapy Program
- Frank A. Campini Foundation
- NIH/National Cancer Institute [T32 5T32CA128583-09]
- Helen Hay Whitney Foundation
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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