Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma

肝细胞癌 表观遗传学 免疫疗法 癌症研究 医学 肿瘤科 生物 内科学 癌症 遗传学 基因
作者
Yalin Tu,Haoran Wu,Chengpeng Zhong,Lei Zhu,Zhewen Xiong,Siyun Chen,Jing Wang,Patrick Pak-Chun Wong,Weiqin Yang,Zhixian Liang,Jiahuan Lu,Shufen Chen,Lingyun Zhang,Yu Feng,Willis Wai-Yiu Si-Tou,Baoyi Yin,Yingnan Lin,Jianxin Liang,Liying Liang,Joaquim S. L. Vong,Weida Ren,Tsz Tung Kwong,Howard Ho‐Wai Leung,Ka‐Fai To,Stephanie Ma,Man Tong,Hanyong Sun,Qiang Xia,Jingying Zhou,Rachel Kerr,Nick La Thangue,Joseph J.�Y. Sung,Stephen L. Chan,Alfred Sze‐Lok Cheng
出处
期刊:Gut [BMJ]
卷期号:: gutjnl-332281
标识
DOI:10.1136/gutjnl-2024-332281
摘要

Background Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. Objective We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). Design We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial ( NCT03419481 ) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. Results HCC patients showing higher HDAC1 / 2 / 3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3 high tumours to ICB therapies, resulting in CD8 + T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ + GZMB + cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Conclusion Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance ( NCT05873244 ).
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