Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
Gut. 2024 Nov 11;73(12):2023-2036. doi: 10.1136/gutjnl-2023-331117.
Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear.
We established hepatocyte-specific transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry.
Hepatocyte-specific tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-γ and Granzyme B CD8 T cells while enriching Arg-1 myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific knockout suppressed tumour growth with increased cytotoxic CD8 T cells and reduced Arg-1 MDSCs, inferring that SQLE promotes immunosuppression in MASH-HCC. Mechanistically, SQLE-driven cholesterol accumulation in tumour microenvironment underlies its effect on CD8 T cells and MDSCs. SQLE and its metabolite, cholesterol, impaired CD8 T cell activity by inducing mitochondrial dysfunction. Cholesterol depletion in vitro abolished the effect of SQLE-overexpressing MASH-HCC cell supernatant on CD8 T cell suppression and MDSC activation, whereas cholesterol supplementation had contrasting functions on CD8 T cells and MDSCs treated with SQLE-knockout supernatant. Targeting SQLE with genetic ablation or pharmacological inhibitor, terbinafine, rescued the efficacy of anti-PD-1 treatment in MASH-HCC models.
SQLE induces an impaired antitumour response in MASH-HCC via attenuating CD8 T cell function and augmenting immunosuppressive MDSCs. SQLE is a promising target in boosting anti-PD-1 immunotherapy for MASH-HCC.
鲨烯环氧酶（SQLE）促进代谢相关脂肪性肝炎相关肝细胞癌（MASH-HCC），但其在调节 MASH-HCC 肿瘤免疫微环境中的作用尚不清楚。
我们建立了肝细胞特异性转基因（tg）和敲除小鼠，它们接受胆碱缺乏高脂饮食加二乙基亚硝胺诱导 MASH-HCC。还在原位和人源化小鼠中确定了 SQLE 的功能。通过单细胞 RNA 测序和流式细胞术分析 SQLE 介导的 MASH-HCC 的免疫景观改变。
与野生型同窝仔相比，肝细胞特异性 tg 小鼠的 MASH-HCC 负担明显增加，同时肿瘤浸润的功能性 IFN-γ和颗粒酶 B CD8 T 细胞减少，而 Arg-1 髓系来源的抑制细胞（MDSCs）丰富。相反，肝细胞特异性敲除抑制肿瘤生长，增加细胞毒性 CD8 T 细胞，减少 Arg-1 MDSCs，这表明 SQLE 促进 MASH-HCC 的免疫抑制。在机制上，SQLE 在肿瘤微环境中驱动胆固醇积累，从而影响 CD8 T 细胞和 MDSCs。SQLE 及其代谢产物胆固醇通过诱导线粒体功能障碍损害 CD8 T 细胞活性。体外胆固醇耗竭消除了 SQLE 过表达 MASH-HCC 细胞上清液对 CD8 T 细胞抑制和 MDSC 激活的影响，而胆固醇补充对用 SQLE 敲除上清液处理的 CD8 T 细胞和 MDSC 具有相反的作用。用遗传消融或药物抑制剂特比萘芬靶向 SQLE，挽救了 MASH-HCC 模型中抗 PD-1 治疗的疗效。
SQLE 通过削弱 CD8 T 细胞功能和增强免疫抑制性 MDSCs，在 MASH-HCC 中诱导受损的抗肿瘤反应。SQLE 是增强抗 PD-1 免疫疗法治疗 MASH-HCC 的有前途的靶点。
