Zhang Zerui, Huang Wenjie, Hu Dian, Jiang Junqing, Zhang Jiaqian, Wu Zhangfan, Wen Junjie, Luo Xiangyuan, Wang Yijun, Sun Mengyu, Li Siwen, Wang Yufei, Liu Danfei, Chen Xiaoping, Zhang Bixiang, Liang Huifang, Li Yiwei, Liu Bifeng, Wang Shuai, Xu Xiao, Nie Yongzhan, Wu Kaichun, Fan Daiming, Xia Limin
Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China.
Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China.
Gut. 2025 Jun 6;74(7):1137-1149. doi: 10.1136/gutjnl-2024-333944.
BACKGROUND: Despite the success of immune checkpoint blockade, a lack of understanding of the hepatocellular carcinoma (HCC) immune microenvironment impedes its development. OBJECTIVE: We aim to elucidate the essential function of E-twenty-six-specific sequence variant 5 (ETV5) in regulating the immune microenvironment in HCC. DESIGN: Humanised mouse models, murine orthotopic models and diethylnitrosamine/carbon tetrachloride (DEN/CCl)-induced HCC models were used to examine the function of ETV5. The downstream targets of ETV5 were screened using chromatin immunoprecipitation sequencing, CUT&Tag and RNA sequencing. Immune cells were examined using flow cytometry and immunofluorescence. S100 calcium-binding protein A9 (S100A9) was targeted by neutralising antibodies. RESULTS: Overexpression of ETV5 in HCC cells facilitated HCC metastasis and immune escape by recruiting and enhancing the immunosuppressive capabilities of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, ETV5 transactivated programmed death ligand 1 (PD-L1) and S100A9 expression. Inhibition of S100A9 or myeloid-specific knockout of toll-like receptor 4 (TLR4)/receptor for advanced glycation endproducts (RAGE), the receptors of S100A9, impeded ETV5-induced PMN-MDSC recruitment. Meanwhile, S100A9 within the tumour microenvironment elevated ETV5 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor-kappa B pathway. Additionally, ETV5 transcriptionally upregulated PD-L1 in MDSCs as well, thereby augmenting their immunosuppressive functions. Myeloid-specific knockout attenuated HCC progression. We developed monoclonal neutralising-S100A9 antibodies that effectively inhibited ETV5-mediated PMN-MDSC infiltration. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy significantly suppressed ETV5-mediated HCC progression. CONCLUSION: ETV5 facilitates HCC progression and metastasis by promoting the recruitment, infiltration and activation of PMN-MDSCs. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy holds great promise as an effective combinational treatment strategy for ETV5-positive HCC.
背景：尽管免疫检查点阻断取得了成功，但对肝细胞癌（HCC）免疫微环境的缺乏了解阻碍了其发展。 目的：我们旨在阐明E-26特异性序列变体5（ETV5）在调节HCC免疫微环境中的重要功能。 设计：使用人源化小鼠模型、小鼠原位模型和二乙基亚硝胺/四氯化碳（DEN/CCl）诱导的HCC模型来研究ETV5的功能。使用染色质免疫沉淀测序、CUT&Tag和RNA测序筛选ETV5的下游靶点。使用流式细胞术和免疫荧光检查免疫细胞。用中和抗体靶向S100钙结合蛋白A9（S100A9）。 结果：HCC细胞中ETV5的过表达通过招募和增强多形核骨髓来源的抑制细胞（PMN-MDSCs）的免疫抑制能力促进HCC转移和免疫逃逸。机制上，ETV5反式激活程序性死亡配体1（PD-L1）和S100A9的表达。抑制S100A9或髓系特异性敲除S100A9受体Toll样受体4（TLR4）/晚期糖基化终产物受体（RAGE）可阻碍ETV5诱导的PMN-MDSC募集。同时肿瘤微环境中的S100A9通过细胞外信号调节激酶（ERK）/核因子-κB途径提高ETV5表达。此外，ETV5在MDSCs中也转录上调PD-L1，从而增强其免疫抑制功能。髓系特异性敲除减弱了HCC进展。我们开发了单克隆中和S100A9抗体，可有效抑制ETV5介导的PMN-MDSC浸润。抗S100A9或TLR4/RAGE抑制剂与抗PD-L1疗法的联合应用显著抑制了ETV5介导的HCC进展。 结论：ETV5通过促进PMN-MDSCs的募集、浸润和激活促进HCC进展和转移。抗S100A9或TLR4/RAGE抑制剂与抗PD-L1疗法的联合应用有望成为ETV5阳性HCC的有效联合治疗策略。
J Immunother Cancer. 2024-9-11
Cell Mol Gastroenterol Hepatol. 2023
Front Immunol. 2025-7-2
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