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Article: Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma
Title | Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma |
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Authors | Tu, YalinWu, HaoranZhong, ChengpengLiu, YanXiong, ZhewenChen, SiyunWang, JingWong, Patrick Pak ChunYang, WeiqinLiang, ZhixianLu, JiahuanChen, ShufenZhang, LingyunFeng, YuSi-Tou, Willis Wai YiuYin, BaoyiLin, YingnanLiang, JianxinLiang, LiyingVong, Joaquim S.L.Ren, WeidaKwong, Tsz TungLeung, HowardTo, Ka FaiMa, StephanieTong, ManSun, HanyongXia, QiangZhou, JingyingKerr, DavidLa Thangue, NickSung, Joseph J.Y.Chan, Stephen LamCheng, Alfred Sze Lok |
Keywords | HEPATOCELLULAR CARCINOMA IMMUNOTHERAPY INTERFERON |
Issue Date | 1-Jan-2024 |
Publisher | BMJ Publishing Group |
Citation | Gut, 2024 How to Cite? |
Abstract | 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 HDAC1/2/3high 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 Identifier | http://hdl.handle.net/10722/355356 |
ISSN | 2023 Impact Factor: 23.0 2023 SCImago Journal Rankings: 8.052 |
DC Field | Value | Language |
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dc.contributor.author | Tu, Yalin | - |
dc.contributor.author | Wu, Haoran | - |
dc.contributor.author | Zhong, Chengpeng | - |
dc.contributor.author | Liu, Yan | - |
dc.contributor.author | Xiong, Zhewen | - |
dc.contributor.author | Chen, Siyun | - |
dc.contributor.author | Wang, Jing | - |
dc.contributor.author | Wong, Patrick Pak Chun | - |
dc.contributor.author | Yang, Weiqin | - |
dc.contributor.author | Liang, Zhixian | - |
dc.contributor.author | Lu, Jiahuan | - |
dc.contributor.author | Chen, Shufen | - |
dc.contributor.author | Zhang, Lingyun | - |
dc.contributor.author | Feng, Yu | - |
dc.contributor.author | Si-Tou, Willis Wai Yiu | - |
dc.contributor.author | Yin, Baoyi | - |
dc.contributor.author | Lin, Yingnan | - |
dc.contributor.author | Liang, Jianxin | - |
dc.contributor.author | Liang, Liying | - |
dc.contributor.author | Vong, Joaquim S.L. | - |
dc.contributor.author | Ren, Weida | - |
dc.contributor.author | Kwong, Tsz Tung | - |
dc.contributor.author | Leung, Howard | - |
dc.contributor.author | To, Ka Fai | - |
dc.contributor.author | Ma, Stephanie | - |
dc.contributor.author | Tong, Man | - |
dc.contributor.author | Sun, Hanyong | - |
dc.contributor.author | Xia, Qiang | - |
dc.contributor.author | Zhou, Jingying | - |
dc.contributor.author | Kerr, David | - |
dc.contributor.author | La Thangue, Nick | - |
dc.contributor.author | Sung, Joseph J.Y. | - |
dc.contributor.author | Chan, Stephen Lam | - |
dc.contributor.author | Cheng, Alfred Sze Lok | - |
dc.date.accessioned | 2025-04-04T00:35:19Z | - |
dc.date.available | 2025-04-04T00:35:19Z | - |
dc.date.issued | 2024-01-01 | - |
dc.identifier.citation | Gut, 2024 | - |
dc.identifier.issn | 0017-5749 | - |
dc.identifier.uri | http://hdl.handle.net/10722/355356 | - |
dc.description.abstract | 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 HDAC1/2/3high 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.language | eng | - |
dc.publisher | BMJ Publishing Group | - |
dc.relation.ispartof | Gut | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | HEPATOCELLULAR CARCINOMA | - |
dc.subject | IMMUNOTHERAPY | - |
dc.subject | INTERFERON | - |
dc.title | Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma | - |
dc.type | Article | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1136/gutjnl-2024-332281 | - |
dc.identifier.pmid | 39486886 | - |
dc.identifier.scopus | eid_2-s2.0-85209379903 | - |
dc.identifier.eissn | 1468-3288 | - |
dc.identifier.issnl | 0017-5749 | - |