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 ).
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
大辉发布了新的文献求助10
刚刚
田様应助坚定自信采纳,获得10
刚刚
青悠完成签到,获得积分20
1秒前
1秒前
情怀应助zzzmmmhhh采纳,获得10
3秒前
icebear完成签到,获得积分10
4秒前
四叶草发布了新的文献求助30
4秒前
李健的小迷弟应助gayfall采纳,获得10
5秒前
楠楠发布了新的文献求助10
5秒前
carbon-dots发布了新的文献求助10
6秒前
木棉完成签到,获得积分10
10秒前
海参完成签到,获得积分10
11秒前
酷波er应助小菇凉采纳,获得10
11秒前
12秒前
赘婿应助潇洒忘幽采纳,获得10
13秒前
传奇3应助枝桠采纳,获得10
14秒前
烦烦烦方法完成签到,获得积分10
16秒前
17秒前
whr0458完成签到,获得积分10
19秒前
卓若之完成签到 ,获得积分10
19秒前
19秒前
完美行云完成签到,获得积分10
20秒前
殊桐完成签到,获得积分10
21秒前
21秒前
21秒前
小笑完成签到,获得积分10
21秒前
Hello应助能干可兰采纳,获得10
21秒前
俭朴山兰发布了新的文献求助10
24秒前
李子木发布了新的文献求助10
24秒前
24秒前
24秒前
Akim应助Xu_W卜采纳,获得10
25秒前
Tong发布了新的文献求助10
26秒前
嘀嘀哒哒发布了新的文献求助10
26秒前
啊啊啊完成签到 ,获得积分10
27秒前
28秒前
无花果应助小千采纳,获得10
28秒前
mingjie发布了新的文献求助10
29秒前
30秒前
算了发布了新的文献求助30
32秒前
高分求助中
The ACS Guide to Scholarly Communication 2500
Sustainability in Tides Chemistry 2000
Pharmacogenomics: Applications to Patient Care, Third Edition 1000
Studien zur Ideengeschichte der Gesetzgebung 1000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Threaded Harmony: A Sustainable Approach to Fashion 810
《粉体与多孔固体材料的吸附原理、方法及应用》(需要中文翻译版,化学工业出版社,陈建,周力,王奋英等译) 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3084389
求助须知:如何正确求助?哪些是违规求助? 2737327
关于积分的说明 7544689
捐赠科研通 2386947
什么是DOI,文献DOI怎么找? 1265702
科研通“疑难数据库(出版商)”最低求助积分说明 613158
版权声明 598320