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Targeting Histone Deacetylase 6 Reprograms Interleukin‐17‐Producing Helper T Cell Pathogenicity and Facilitates Immunotherapies for...,Hepatology, 1 Jun 2020

Updated: 2020-06-01

Hepatology, 1 June, 2020, DOI:https://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 and Pengyuan Yang

 

Abstract

 

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 (TH17) cell pathogenicity and the antitumor immune response, dependent on its deacetylase activity.

 

Approach and Results

 

Adoptive transfer of HDAC6‐deficient TH17 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 TH17 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 (RoRγt), the transcription factor of TH17 cell. This regulation of HDAC6 for murine and human TH17 cell is highly conserved.

 

Conclusions

 

These results demonstrate that targeting the cytosolic HDAC6–FoxO1 axis reprograms the pathogenicity and antitumor response of TH17 cells in HCC, with a pathogenicity‐driven responsiveness to facilitate immunotherapies

 

Article link:https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30960

 

 

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