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

TitlePharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma
Authors
KeywordsHEPATOCELLULAR CARCINOMA
IMMUNOTHERAPY
INTERFERON
Issue Date1-Jan-2024
PublisherBMJ Publishing Group
Citation
Gut, 2024 How to Cite?
AbstractBackground: 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 HDAC1/2/3high 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).
Persistent Identifierhttp://hdl.handle.net/10722/355356
ISSN
2023 Impact Factor: 23.0
2023 SCImago Journal Rankings: 8.052

 

DC FieldValueLanguage
dc.contributor.authorTu, Yalin-
dc.contributor.authorWu, Haoran-
dc.contributor.authorZhong, Chengpeng-
dc.contributor.authorLiu, Yan-
dc.contributor.authorXiong, Zhewen-
dc.contributor.authorChen, Siyun-
dc.contributor.authorWang, Jing-
dc.contributor.authorWong, Patrick Pak Chun-
dc.contributor.authorYang, Weiqin-
dc.contributor.authorLiang, Zhixian-
dc.contributor.authorLu, Jiahuan-
dc.contributor.authorChen, Shufen-
dc.contributor.authorZhang, Lingyun-
dc.contributor.authorFeng, Yu-
dc.contributor.authorSi-Tou, Willis Wai Yiu-
dc.contributor.authorYin, Baoyi-
dc.contributor.authorLin, Yingnan-
dc.contributor.authorLiang, Jianxin-
dc.contributor.authorLiang, Liying-
dc.contributor.authorVong, Joaquim S.L.-
dc.contributor.authorRen, Weida-
dc.contributor.authorKwong, Tsz Tung-
dc.contributor.authorLeung, Howard-
dc.contributor.authorTo, Ka Fai-
dc.contributor.authorMa, Stephanie-
dc.contributor.authorTong, Man-
dc.contributor.authorSun, Hanyong-
dc.contributor.authorXia, Qiang-
dc.contributor.authorZhou, Jingying-
dc.contributor.authorKerr, David-
dc.contributor.authorLa Thangue, Nick-
dc.contributor.authorSung, Joseph J.Y.-
dc.contributor.authorChan, Stephen Lam-
dc.contributor.authorCheng, Alfred Sze Lok-
dc.date.accessioned2025-04-04T00:35:19Z-
dc.date.available2025-04-04T00:35:19Z-
dc.date.issued2024-01-01-
dc.identifier.citationGut, 2024-
dc.identifier.issn0017-5749-
dc.identifier.urihttp://hdl.handle.net/10722/355356-
dc.description.abstractBackground: 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 HDAC1/2/3high 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).-
dc.languageeng-
dc.publisherBMJ Publishing Group-
dc.relation.ispartofGut-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectHEPATOCELLULAR CARCINOMA-
dc.subjectIMMUNOTHERAPY-
dc.subjectINTERFERON-
dc.titlePharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1136/gutjnl-2024-332281-
dc.identifier.pmid39486886-
dc.identifier.scopuseid_2-s2.0-85209379903-
dc.identifier.eissn1468-3288-
dc.identifier.issnl0017-5749-

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