Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy.

IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Gut Pub Date : 2024-12-12 DOI:10.1136/gutjnl-2024-333154
Yating Zhang, Mingxu Xie, Jun Wen, Cong Liang, Qian Song, Weixin Liu, Yali Liu, Yang Song, Harry Cheuk Hay Lau, Alvin Ho-Kwan Cheung, Kwan Man, Jun Yu, Xiang Zhang
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Abstract

Background: Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD).

Objective: We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC).

Design: Hepatocyte-specific Tm6sf2 knockout (Tm6sf2 ∆hep) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance.

Results: TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific Tm6sf2 knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of Tm6sf2 knockout was verified in orthotopic MASLD-HCC mice, while mice bearing Tm6sf2-overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)+CD8+ T cells in the tumours of Tm6sf2 ∆hep mice and orthotopic Tm6sf2 knockout mice, while the tumour-suppressive effect of Tm6sf2 was abolished after depleting CD8+ T cells. The correlation between TM6SF2 and CD8+ T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-κB signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8+ T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects of Tm6sf2 knockout in mice. Moreover, introducing Tm6sf2 by adenovirus improved immunotherapy response against MASLD-HCC in mice.

Conclusion: Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8+ T cells via NF-κB-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.

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背景:跨膜6超家族成员2(TM6SF2)对代谢功能障碍相关性脂肪性肝病(MASLD)具有保护作用:我们旨在研究肝脏TM6SF2在MASLD相关肝细胞癌(HCC)中的机制作用和治疗潜力:设计:用高脂肪/高胆固醇(HFHC)饮食或亚硝胺加HFHC饮食喂养肝细胞特异性Tm6sf2基因敲除(Tm6sf2 ∆hep)小鼠,诱导MASLD-HCC。此外,还对正位 MASLD-HCC 小鼠的 TM6SF2 功能进行了评估。研究还纳入了人类 MASLD-HCC 标本,以评估其临床意义:结果:与 MASLD-HCC 患者的邻近正常组织相比,肿瘤中的 TM6SF2 下调。肝细胞特异性 Tm6sf2 基因敲除会加剧饮食诱导或饮食诱导和致癌物质诱导的 MASLD-HCC 小鼠肿瘤的形成。Tm6sf2基因敲除对肿瘤的促进作用在正位MASLD-HCC小鼠中得到了验证,而携带Tm6sf2基因表达的肿瘤小鼠则表现出相反的表型。我们观察到 Tm6sf2 ∆hep 小鼠和正位 Tm6sf2 基因敲除小鼠的肿瘤中γ干扰素(IFN-γ)+CD8+ T 细胞减少,而在消耗 CD8+ T 细胞后,Tm6sf2 的肿瘤抑制作用消失。在人类 MASLD-HCC 组织中证实了 TM6SF2 与 CD8+ T 细胞的相关性,推断 TM6SF2 可促进抗肿瘤免疫。从机理上讲,TM6SF2直接与IKKβ结合,抑制NF-κB信号通路,减少白细胞介素(IL)-6的分泌,从而激活细胞毒性CD8+ T细胞。IL-6中和可消除Tm6sf2基因敲除对小鼠肿瘤的促进作用和免疫抑制作用。此外,通过腺病毒引入Tm6sf2还能改善小鼠对MASLD-HCC的免疫治疗反应:结论:肝脏 TM6SF2 可保护小鼠免受 MASLD-HCC 感染,并通过 NF-κB-IL-6 轴激活细胞毒性 CD8+ T 细胞。TM6SF2是使MASLD-HCC对免疫疗法敏感的一种有前途的策略。
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来源期刊
Gut
Gut 医学-胃肠肝病学
CiteScore
45.70
自引率
2.40%
发文量
284
审稿时长
1.5 months
期刊介绍: Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts. As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.
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