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Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver

Abstract

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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Data availability

All data in this study are available in the text and its Supplementary Information files. The data that support the findings of this study are available from the corresponding authors upon reasonable request. The RNAseq and scRNAseq data analyzed in this study were accessed with the Gene Expression Omnibus (GEO) series accession numbers: GSE135251 and GSE159977.

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Acknowledgements

We acknowledge Prof. Lars Zender and Prof. Tim F. Greten for their kind gift of the RIL-175 HCC cell line. This project is supported by the University Grants Committee through the Collaborative Research Fund (C4045-18W), AstraZeneca Research Program (2017), General Research Fund (14105419, 14104820), the Li Ka Shing Foundation, and the Terry Fox Foundation.

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Contributions

WT, JZ, and ASLC conceived the study. WT and JZ conducted experiments, analyzed, and interpreted data. HW assisted with bioinformatics analysis. WY, YF, HW, MTSM, LZ, ZL, XL, ZX, XZ, J.Wang, J.Lu., J.Li., and XT assisted with animal experiments. HS, PCY, YH, HML, CCHL, HHWL, AWHC, KFT, J.Wong, PBSL, KKCN, SKHW, VWSW, and APSK. provided patient materials, acquired clinical data, assisted in analyzing NKT cell frequency in patient specimens and interpreted with clinical data. WT, JZ, and ASLC wrote the manuscript. JZ, PBSL, KKCN, VWSW, APSK, JJYS, and ASLC reviewed and edited the manuscript. JZ, JJYS, and ASLC acquired funding for the study. JZ and ASLC supervised the study. All authors read and provided feedback on the manuscript.

Corresponding authors

Correspondence to Jingying Zhou or Alfred S. L. Cheng.

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Competing interests

JZ and ASLC received the funding support and drug (vistusertib) from AstraZeneca. VWSW has consultancy in 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Inventiva, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions and Terns; has lectures in Abbott, AbbVie, Bristol-Myers Squibb, Echosens, Gilead Sciences and Novo Nordisk; received research grants from Gilead Sciences; and holds stock as co-founder of Illuminatio Medical Technology Limited. The other authors declare no competing interests.

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Tang, W., Zhou, J., Yang, W. et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol 19, 834–847 (2022). https://doi.org/10.1038/s41423-022-00872-3

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Keywords

  • NAFLD
  • NKT cells
  • HCC
  • mTOR
  • cholesterol

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