摘要
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。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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