miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate

作者：Yun Ji, Jessica Fioravanti, Wei Zhu, Hongjun Wang, Tuoqi Wu, Jinhui Hu, Neal E. Lacey, Sanjivan Gautam, John B. Le Gall, Xia Yang, James D. Hocker, Thelma M. Escobar, Shan He, Stefania Dell’Orso, Nga Voong Hawk, Veena Kapoor, William G. Telford, Luciano Di Croce, Stefan A. Muljo, Yi Zhang, Vittorio Sartorelli, Luca Gattinoni · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-09882-8 · 被引用次数：84 · 研究领域：Epigenetics and DNA Methylation、Immunotherapy and Immune Responses、Histone Deacetylase Inhibitors Research

Abstract T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8 + T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8 + T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155–Phf19–PRC2 as a pivotal axis regulating CD8 + T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8 + T cell fate.