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

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 ZhangVittorio Sartorelli, Luca Gattinoni

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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.

Original language	English (US)
Article number	2157
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09882-8
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Ji, Y., Fioravanti, J., Zhu, W., Wang, H., Wu, T., Hu, J., Lacey, N. E., Gautam, S., Le Gall, J. B., Yang, X., Hocker, J. D., Escobar, T. M., He, S., Dell’Orso, S., Hawk, N. V., Kapoor, V., Telford, W. G., Di Croce, L., Muljo, S. A., ... Gattinoni, L. (2019). miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8⁺ T cell fate. Nature communications, 10(1), [2157]. https://doi.org/10.1038/s41467-019-09882-8

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 & Gattinoni, L 2019, 'miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8⁺ T cell fate', Nature communications, vol. 10, no. 1, 2157. https://doi.org/10.1038/s41467-019-09882-8

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

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.",

author = "Yun Ji and Jessica Fioravanti and Wei Zhu and Hongjun Wang and Tuoqi Wu and Jinhui Hu and Lacey, {Neal E.} and Sanjivan Gautam and {Le Gall}, {John B.} and Xia Yang and Hocker, {James D.} and Escobar, {Thelma M.} and Shan He and Stefania Dell{\textquoteright}Orso and Hawk, {Nga V.} and Veena Kapoor and Telford, {William G.} and {Di Croce}, Luciano and Muljo, {Stefan A.} and Yi Zhang and Vittorio Sartorelli and Luca Gattinoni",

note = "Funding Information: This research was supported by the Intramural Research Programs of the US National Institutes of Health, National Cancer Institute (ZIABC011480), National Institute of Arthritis, Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases. We thank K. Hanada for providing B16 (H-2b)-hgp100. This work used the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). Publisher Copyright: {\textcopyright} 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2019",

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day = "1",

doi = "10.1038/s41467-019-09882-8",

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T1 - miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate

AU - Ji, Yun

AU - Fioravanti, Jessica

AU - Zhu, Wei

AU - Wang, Hongjun

AU - Wu, Tuoqi

AU - Hu, Jinhui

AU - Lacey, Neal E.

AU - Gautam, Sanjivan

AU - Le Gall, John B.

AU - Yang, Xia

AU - Hocker, James D.

AU - Escobar, Thelma M.

AU - He, Shan

AU - Dell’Orso, Stefania

AU - Hawk, Nga V.

AU - Kapoor, Veena

AU - Telford, William G.

AU - Di Croce, Luciano

AU - Muljo, Stefan A.

AU - Zhang, Yi

AU - Sartorelli, Vittorio

AU - Gattinoni, Luca

N1 - Funding Information: This research was supported by the Intramural Research Programs of the US National Institutes of Health, National Cancer Institute (ZIABC011480), National Institute of Arthritis, Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases. We thank K. Hanada for providing B16 (H-2b)-hgp100. This work used the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). Publisher Copyright: © 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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

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