PT - JOURNAL ARTICLE AU - Yang, Weiqin AU - Feng, Yu AU - Zhou, Jingying AU - Cheung, Otto Ka-Wing AU - Cao, Jianquan AU - Wang, Jing AU - Tang, Wenshu AU - Tu, Yalin AU - Xu, Liangliang AU - Wu, Feng AU - Tan, Zhiwu AU - Sun, Hanyong AU - Tian, Yuan AU - Wong, John AU - Lai, Paul Bo-San AU - Chan, Stephen Lam AU - Chan, Anthony Wing-Hung AU - Tan, Patrick Boon-Ooi AU - Chen, Zhiwei AU - Sung, Joseph Jao-Yiu AU - Yip, Kevin Yuk-Lap AU - To, Ka-Fai AU - Cheng, Alfred Sze-Lok TI - A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma AID - 10.1126/scitranslmed.aaz6804 DP - 2021 Apr 07 TA - Science Translational Medicine PG - eaaz6804 VI - 13 IP - 588 4099 - http://stm.sciencemag.org/content/13/588/eaaz6804.short 4100 - http://stm.sciencemag.org/content/13/588/eaaz6804.full AB - A challenge for cancer immunotherapy is the need to turn cold, immune cell–excluded tumors into hot, inflamed tumors. Here, Yang et al. investigated the role of histone deacetylase 8 (HDAC8) in maintaining immune cell–excluded tumors. The authors showed that selective pharmacological inhibition of HDAC8 changed the epigenetic landscape of hepatocellular carcinoma cells, leading to production of T cell–recruiting chemokines. Treatment of hepatocellular carcinoma–bearing mice with the selective HDAC8 inhibitor resulted in increased infiltration of CD8+ T cells. Further, treatment with the HDAC8 inhibitor and immune checkpoint blockade led to enhanced control of tumors with no evidence of toxicity. Thus, epigenetic reprogramming used in combination with immunotherapy may be a promising approach for treating hepatocellular carcinomas and other immunologically cold tumors.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.