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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 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.

SUBMITTER: Ji Y

PROVIDER: S-EPMC6517388 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Ji Yun Y Fioravanti Jessica J Zhu Wei W Wang Hongjun H Wu Tuoqi T Hu Jinhui J Lacey Neal E NE Gautam Sanjivan S Le Gall John B JB Yang Xia X Hocker James D JD Escobar Thelma M TM He Shan S Dell'Orso Stefania S Dell'Orso Stefania S Hawk Nga V NV Kapoor Veena V Telford William G WG Di Croce Luciano L Muljo Stefan A SA Zhang Yi Y Sartorelli Vittorio V Gattinoni Luca L

Nature communications 20190514 1

T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8<sup>+</sup> 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 orchestrate ...[more]

PMID: 31089138

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Project description:BackgroundCheckpoint blockade immunotherapy, represented by PD-1 or PD-L1 antibody treatment, has been of tremendous success in clinical practice. However, the low clinical response rate and lack of biomarkers for prediction of the immune response limit the clinical application of anti-PD-1 immunotherapy. Our recent work showed that a combination of low-dose decitabine and PD-1-ab significantly improved the complete response (CR) rate of cHL patients from 32 to 71%, which indicates that there is a significant correlation between epigenetic regulation and the clinical response to immunotherapy.MethodsWe recruited two groups of Hodgkin lymphoma patients who were treated with anti-PD-1 and DAC+anti-PD-1. CD8+ T cells were isolated from the patients' peripheral blood, DNA methylation was analyzed by EPIC, the expression profile was analyzed by RNA-seq, and multigroup analysis was performed with IPA and GSEA functional annotations. We explored the effect of DAC on the function of CD8+ T cells in the blood, spleen, tumor and lymph nodes using a mouse model. Furthermore, we explored the function of Tils in the tumor microenvironment. Then, we constructed Runx3-knockout mice to confirm the T-cell-specific function of Runx3 in CD8+ T cells and analyzed various subtypes of T cells and cytokines using mass cytometry (CyTOF).ResultsMultiomics analysis identified that DNA methylation reprogramming of Runx3 was a crucial mediator of CD8+ T-cell function. Multiomics data showed that reversal of methylation of the Runx3 promoter promoted the infiltration of CD8+ TILs and mitigated the exhaustion of CD8+ T cells. Furthermore, experiments on tissue-specific Runx3-knockout mice showed that Runx3 deficiency reduced CD8+ T infiltration and the differentiation of effector T and memory T cells. Furthermore, Runx3 deficiency significantly decreased CCR3 and CCR5 levels. Immunotherapy experiments in Runx3 conditional knockout mice showed that DAC could not reverse the resistance of anti-PD-1 in the absence of Runx3. Moreover, both our clinical data and data from TISIDB showed that Runx3 could be a potential biomarker for immunotherapy to predict the clinical response rate.ConclusionWe demonstrate that the DNA methylation of Runx3 plays a critical role in CD8+ T-cell infiltration and differentiation during decitabine-primed PD-1-ab immunotherapy, which provides a supporting mechanism for the essential role of epiregulation in immunotherapy.

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

Publications

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

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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