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Tang, Wenshu; Zhou, Jingying; Yang, Weiqin; Feng, Yu; Wu, Haoran; Mok, Myth T S; Zhang, Lingyun; Liang, Zhixian; Liu, Xiaoyu; Xiong, Zhewen; Zeng, Xuezhen; Wang, Jing; Lu, Jiahuan; Li, Jingqing; Sun, Hanyong; Tian, Xiaoyu; Yeung, Philip Chun; Hou, Yong; Lee, Heung Man; Lam, Candice C H; Leung, Howard H W; Chan, Anthony W H; To, Ka Fai; Wong, John; Lai, Paul B S; Ng, Kelvin K C; Wong, Simon K H; Wong, Vincent W S; Kong, Alice P S; Sung, Joseph J Y; Cheng, Alfred S L
Cellular & Molecular Immunology/Cellular & molecular immunology, 07/2022, Letnik: 19, Številka: 7Journal Article
Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8 T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.
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in: SICRIS
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