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

Ji Y, Fioravanti J, Zhu W, Wang H, Wu T, Hui J, Lacey NE, Gautam S, Le Gall JB, Yang X, Hocker JD, Escobar TM, He S, Dell'Orso S, Hawk N, Kapoor V, Telford WG, Di Croce L, Muljo SA, Zhang Y, Sartorelli V, Gattinoni L (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 10

Article Number: 2157

Journal Issue: 1

DOI: 10.1038/s41467-019-09882-8

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 senescvbence 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.

Involved external institutions

National Cancer Institute (NCI) US United States (USA) (US) US National Institutes of Health (NIH) US United States (USA) (US) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona ES Spain (ES) Temple University US United States (USA) (US) Inova Translational Medicine Institute (ITMI) US United States (USA) (US) National Human Genome Research Institute (NHGRI) US United States (USA) (US)

How to cite

APA:

Ji, Y., Fioravanti, J., Zhu, W., Wang, H., Wu, T., Hui, J.,... Gattinoni, L. (2019). miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate. Nature Communications, 10(1). https://doi.org/10.1038/s41467-019-09882-8

MLA:

Ji, Yun, et al. "miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate." Nature Communications 10.1 (2019).

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