A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma.

Abstract

Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T cell-dependent manner. The tumor-suppressive effect of selective HDAC8 inhibition was abrogated by CD8+ T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell-trafficking chemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mouse models. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8+ T cells and potentiated eradication of established hepatomas by anti-PD-L1 therapy without evidence of toxicity. Mice treated with HDAC8 and PD-L1 coblockade were protected against subsequent tumor rechallenge as a result of the induction of memory T cells and remained tumor-free for greater than 15 months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durable responses to ICB by co-opting adaptive immunity through enhancer reprogramming.

• Authors: Weiqin Yang, Yu Feng, Jingying Zhou, Otto Ka-Wing Cheung, Jianquan Cao, Jing Wang, Wenshu Tang, Yalin Tu, Liangliang Xu, Feng Wu, Zhiwu Tan, Hanyong Sun, Yuan Tian, John Wong, Paul Bo-San Lai, Stephen Lam Chan, Anthony Wing-Hung Chan, Patrick Boon-Ooi Tan, Zhiwei Chen, Joseph Jao-Yiu Sung, Kevin Yuk-Lap Yip, Ka-Fai To, Alfred Sze-Lok Cheng
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 588 (04 07 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33827976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Histone Deacetylase Inhibitors
• Immune Checkpoint Inhibitors
• Repressor Proteins
• HDAC8 protein, human
• Histone Deacetylases

Topics

• Animals
• CD8-Positive T-Lymphocytes
• Carcinoma, Hepatocellular (drug therapy, immunology)
• Cell Line, Tumor
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Liver Neoplasms (drug therapy, immunology)
• Mice
• Repressor Proteins