Targeting Histone Deacetylase 6 Reprograms Interleukin‐17‐Producing Helper T Cell Pathogenicity and Facilitates..., Hepatology, 01 Feb 2020

发布时间:2020-02-01

Hepatology, 01 February, 2020,DOI:http://dx.doi.org/10.1002/hep.30960

Targeting Histone Deacetylase 6 Reprograms Interleukin‐17‐Producing Helper T Cell Pathogenicity and Facilitates Immunotherapies for Hepatocellular Carcinoma

Weinan Qiu, Bin Wang, Yanan Gao, Yuan Tian, Meijie Tian, Yuanying Chen, Li Xu, Tso‐Pang Yao, Peng Li, Pengyuan Yang

Summary

Background and Aims Hepatocellular carcinoma (HCC) is often accompanied by resistance to immunotherapies despite the presence of tumor-infiltrating lymphocytes. We report that histone deacetylase 6 (HDAC6) represses interleukin-17 (IL-17)-producing helper T (T(H)17) cell pathogenicity and the antitumor immune response, dependent on its deacetylase activity.

Approach and Results Adoptive transfer of HDAC6-deficient T(H)17 cells impedes HCC growth, dependent on elevated IL-17A, by enhancing the production of antitumor cytokine and cluster of differentiation 8-positive (CD8+) T cell-mediated antitumor responses. Intriguingly, HDAC6-depleted T cells trigger programmed cell death protein 1 (PD-1)-PD-1 ligand 1 expression to achieve a strong synergistic effect to sensitize advanced HCC to an immune checkpoint blocker, while blockade of IL-17A partially suppresses it. Mechanistically, HDAC6 limits T(H)17 pathogenicity and the antitumor effect through regulating forkhead box protein O1 (FoxO1). HDAC6 binds and deacetylates cytosolic FoxO1 at K242, which is required for its nuclear translocation and stabilization to repress retinoic acid-related orphan receptor gamma (RoR gamma t), the transcription factor of T(H)17 cell. This regulation of HDAC6 for murine and human T(H)17 cell is highly conserved.

Conclusions These results demonstrate that targeting the cytosolic HDAC6-FoxO1 axis reprograms the pathogenicity and antitumor response of T(H)17 cells in HCC, with a pathogenicity-driven responsiveness to facilitate immunotherapies

文章链接:https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.30960

 

 


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