癌症研究
HDAC8型
免疫检查点
生物
免疫系统
免疫疗法
乙酰化
免疫学
组蛋白脱乙酰基酶
组蛋白
生物化学
基因
作者
Weiqin Yang,Yuanming Feng,Jingying Zhou,Otto Ka-Wing Cheung,Jianquan Cao,Jing Wang,WM Tang,Yalin Tu,Liangliang Xu,Feng Wu,Zhiwu Tan,Hanyong Sun,Yuan Tian,John Wong,Paul Lai,Stephen L. Chan,Anthony Wing‐Hung Chan,Patrick Tan,Zhiwei Chen,Joseph J.Y. Sung,Kevin Y. Yip,Ka‐Fai To,Alfred Sze‐Lok Cheng
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-04-07
卷期号:13 (588)
被引量:59
标识
DOI:10.1126/scitranslmed.aaz6804
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI