A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma
Refereed conference paper presented and published in conference proceedings
香港中文大學研究人員
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摘要Insufficient T cell infiltration into non-inflamed tumors, such as hepatocellularcarcinoma (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 remainincompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8),a histone H3 lysine 27 (H3K27)-specific isozyme over-expressed in a variety of human cancers, thwarts HCCtumorigenicity in a T cell-dependent manner. The tumor-suppressive effect of selective HDAC8 inhibitionwas abrogated by CD8+ T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling ofhuman HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1,251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulationof HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell-traffickingchemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mousemodels. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8+ T cellsand potentiated eradication of established hepatomas by anti-PD-L1 therapy without evidence of toxicity.Importantly, mice treated with HDAC8 and PD-L1 co-blockade were protected against subsequent tumorre-challenge as a result of the induction of memory T cells and remained tumor-free for greater than 15months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durableresponses to ICB by co-opting adaptive immunity through enhancer reprogramming.
著者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
會議名稱The Korean Association of Immunologists International Meeting 2021
會議開始日02.06.2021
會議完結日04.06.2021
會議地點Online
會議國家/地區韓國
出版年份2021
月份6
日期2
語言美式英語
