1. miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8 + T cell fate.
- Author
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Ji Y, Fioravanti J, Zhu W, Wang H, Wu T, Hu J, Lacey NE, Gautam S, Le Gall JB, Yang X, Hocker JD, Escobar TM, He S, Dell'Orso S, Hawk NV, Kapoor V, Telford WG, Di Croce L, Muljo SA, Zhang Y, Sartorelli V, and Gattinoni L
- Subjects
- Adoptive Transfer methods, Animals, 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 therapy, Mice, Mice, Inbred C57BL, Mice, Knockout, 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 therapy, Transcription Factors genetics, Transcription Factors immunology, CD8-Positive T-Lymphocytes immunology, Melanoma, Experimental immunology, MicroRNAs metabolism, Skin Neoplasms immunology, Transcription Factors metabolism
- 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.- Published
- 2019
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