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; Luca Gattinoni

doi:10.1038/s41467-019-09882-8

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

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

Authors

Yun Ji^{1

2}, Jessica Fioravanti³, Wei Zhu⁴, Hongjun Wang⁵, Tuoqi Wu⁶, Jinhui Hu³, Neal E Lacey³, Sanjivan Gautam³, John B Le Gall³, Xia Yang³, James D Hocker³, Thelma M Escobar⁷, Shan He⁸, Stefania Dell'Orso⁵, Nga V Hawk³, Veena Kapoor³, William G Telford³, Luciano Di Croce^{9

10

11}, Stefan A Muljo⁷, Yi Zhang⁸, Vittorio Sartorelli⁵, Luca Gattinoni¹²

Affiliations

¹ Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. [email protected].
² Cellular Biomedicine Group (CBMG), Gaithersburg, MD, 20877, USA. [email protected].
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. [email protected].

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.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Adoptive Transfer / methods
Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / transplantation
Cell Differentiation / genetics
Cell Differentiation / immunology
Cellular Senescence / genetics
Cellular Senescence / immunology
Epigenesis, Genetic / immunology
Female
Gene Expression Regulation, Neoplastic
Humans
Melanoma, Experimental / genetics
Melanoma, Experimental / immunology*
Melanoma, Experimental / therapy
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs / metabolism*
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / metabolism
Polycomb Repressive Complex 2 / immunology
Polycomb Repressive Complex 2 / metabolism
Skin Neoplasms / genetics
Skin Neoplasms / immunology*
Skin Neoplasms / therapy
Transcription Factors / genetics
Transcription Factors / immunology
Transcription Factors / metabolism*

Substances

MicroRNAs
Mirn155 microRNA, mouse
Phf19 protein, mouse
Transcription Factors
Polycomb Repressive Complex 2
Inpp5d protein, mouse
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Grants and funding

ZIA BC011480/Intramural NIH HHS/United States