Article
Author: Vong, Joaquim S L ; Yang, Weiqin ; Chan, Stephen Lam ; Cheng, Alfred Sze-Lok ; Kerr, David ; Wong, Patrick Pak-Chun ; Xiong, Zhewen ; Lin, Yingnan ; Sun, Hanyong ; Tong, Man ; Sung, Joseph J Y ; Ren, Weida ; Yin, Baoyi ; Feng, Yu ; Wang, Jing ; Si-Tou, Willis Wai-Yiu ; Chen, Siyun ; Liang, Liying ; Leung, Howard ; Zhong, Chengpeng ; Ma, Stephanie ; Zhang, Lingyun ; Zhou, Jingying ; Liang, Zhixian ; To, Ka Fai ; Kwong, Tsz Tung ; Xia, Qiang ; Lu, Jiahuan ; La Thangue, Nick ; Liang, Jianxin ; Liu, Yan ; Wu, Haoran ; Chen, Shufen ; Tu, Yalin
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 higherHDAC1/2/3expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3hightumours 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).