药理激活 STAT1-GSDME 热解回路可加强肝细胞癌的表观遗传免疫疗法

IF 23 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Gut Pub Date : 2024-11-01 DOI:10.1136/gutjnl-2024-332281

Yalin Tu, Haoran Wu, Chengpeng Zhong, Yan Liu, 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 Leung, Ka Fai To, Stephanie Ma, Man Tong, Hanyong Sun, Qiang Xia, Jingying Zhou, David Kerr, Nick La Thangue, Joseph J Y Sung, Stephen Lam Chan, Alfred Sze-Lok Cheng

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引用次数: 0

摘要

背景基因组筛选发现了免疫检查点阻断疗法（ICB）难治性肿瘤中干扰素-γ（IFNγ）通路的缺陷。然而，人们对该通路的非突变调控和治疗开发的可逆性仍然知之甚少。目的我们旨在确定与ICB耐药相关的可药物组蛋白去乙酰化酶（HDACs），并为肝细胞癌（HCC）患者开发一种易于转化的联合治疗方法。设计我们通过单细胞 RNA 测序将 pembrolizumab 试验（[NCT03419481][1]）中 HCC 患者的预后结果与肿瘤细胞中所有 HDAC 同工酶的表达相关联。我们利用免疫图谱分析、单细胞多组学和染色质免疫沉淀测序，并通过基因修饰和共培养系统验证，研究了选择性 HDAC 抑制剂在 4 种抗 ICB 正位和自发模型中的疗效和作用机制。结果 HDAC1 / 2 / 3 表达较高的 HCC 患者表现出 IFNγ 信号不足，接受 ICB 治疗后存活率较低。选择性 I 类 HDAC 抑制剂 CXD101 的瞬时治疗可使 HDAC1/2/3 高表达的肿瘤对 ICB 疗法重新敏感，从而产生依赖 CD8+T 细胞的抗肿瘤和记忆 T 细胞反应。从机理上讲，CXD101与ICB协同作用，通过增强染色质可及性和IFNγ响应基因的H3K27超乙酰化，刺激STAT1驱动的抗肿瘤免疫。IFNγ+GZMB+细胞毒性淋巴细胞的瘤内招募进一步促进了CXD101诱导的Gasdermin E（GSDME）的裂解，从而以STAT1依赖性的方式触发了热休克。值得注意的是，GSDME 的缺失模拟了 STAT1 基因敲除，通过挫败热蛋白和 IFNγ 反应，取消了 CXD101-ICB 联合疗法的抗肿瘤疗效和生存益处。结论我们的免疫表观遗传学策略利用 IFNγ 介导的网络来增强癌症-免疫循环，揭示了 STAT1-GSDME 自强化热解回路，为正在进行的应对 ICB 抗药性的 II 期试验提供了机理基础 ([NCT05873244][2])。如有合理要求，可提供相关数据。[1]:/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]:/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom

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

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][1]) 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 HDAC1/2/3high 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][2]). Data are available on reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom

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来源期刊

Gut 医学-胃肠肝病学

CiteScore

45.70

自引率

2.40%

发文量

284

审稿时长

1.5 months

期刊介绍： Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts. As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.