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Nat Commun. 2019 May 14;10(1):2157. doi: 10.1038/s41467-019-09882-8.

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

Author information

1
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. yji365@gmail.com.
2
Cellular Biomedicine Group (CBMG), Gaithersburg, MD, 20877, USA. yji365@gmail.com.
3
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
4
Department of Bioinformatics, Inova Translational Medicine Institute, Fairfax, VA, 22031, USA.
5
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
6
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
7
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
8
Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, 19140, USA.
9
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain.
10
Universitat Pompeu Fabra (UPF), Barcelona, 08003, Spain.
11
ICREA, Pg. Lluis Companys 23, 08010, Barcelona, Spain.
12
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. gattinol@mail.nih.gov.

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.

PMID:
31089138
PMCID:
PMC6517388
DOI:
10.1038/s41467-019-09882-8
[Indexed for MEDLINE]
Free PMC Article

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