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

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 V. Hawk, Veena Kapoor, William G. Telford, Luciano Di Croce, Stefan A. Muljo, Yi Zhang, Vittorio Sartorelli and Luca Gattinoni ()
Additional contact information
Yun Ji: National Institutes of Health
Jessica Fioravanti: National Institutes of Health
Wei Zhu: Inova Translational Medicine Institute
Hongjun Wang: National Institutes of Health
Tuoqi Wu: National Institutes of Health
Jinhui Hu: National Institutes of Health
Neal E. Lacey: National Institutes of Health
Sanjivan Gautam: National Institutes of Health
John B. Le Gall: National Institutes of Health
Xia Yang: National Institutes of Health
James D. Hocker: National Institutes of Health
Thelma M. Escobar: National Institutes of Health
Shan He: Temple University
Stefania Dell’Orso: National Institutes of Health
Nga V. Hawk: National Institutes of Health
Veena Kapoor: National Institutes of Health
William G. Telford: National Institutes of Health
Luciano Di Croce: The Barcelona Institute of Science and Technology
Stefan A. Muljo: National Institutes of Health
Yi Zhang: Temple University
Vittorio Sartorelli: National Institutes of Health
Luca Gattinoni: National Institutes of Health

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09882-8

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