IDDF2019-ABS-0221 Metabolic-immunoregulatory role of mTOR signaling in NAFLD-associated hepatocellular carcinoma. (7th June 2019)

• Record Type: Journal Article
• Authors: Tang, Wenshu; Zhou, Jingying; Yang, Weiqin; Feng, Yu; Cheng, Alfred SL
• Is Part Of: Gut. Volume 68(2019)Supplement 1
• Page Start: A55
• Page End: A56
• Publication Date: 2019-06-07
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2019-IDDFAbstracts.100
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background and objective: Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer deaths worldwide. Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disorders from simple steatosis to non-alcoholic steatohepatitis (NASH). Driven by the epidemics of obesity and diabetes, it is anticipated that NAFLD will become the most important cause of HCC. Activation of mammalian target of rapamycin (mTOR) pathway in NAFLD has been shown to promote deregulated lipid/glucose metabolism, immunosuppression and tumorigenesis. Methods: To fully decipher the anti-immune surveillance functions of mTOR pathway in NAFLD-associated HCC, we performed immune cell profiling and signaling characterization in a high-fat high-carbohydrate diet (HFHC)-induced obesity and NASH murine model. Results: We uncovered activation of mTORC1 signaling cascade and specific reduction in cytolytic natural killer T (NKT) cells, which subsequently enhanced tumor growth of orthotopically-implanted HCC tumor cells. Notably, treatment of the mTORC1/C2 dual kinase inhibitor vistusertib (AZD2014), currently undergone phase I/II clinical trials, not only abrogated mTORC1/SREBP2 signaling and cholesterol levels, but also derepressed the cytolytic NKT cells in blood and liver leading to reduced tumorigenicity. Furthermore, NKT cells inactivation by a specific antibody targeting the CD1d receptor abolished anti-tumor effects of vistusertib. Conclusions: Collectively, this study elucidates the metabolic-immunosuppressive role of mTOR signaling in NAFLD-associated HCC and provides insights into the development of therapeutic strategies against the mTOR-reinforced NAFLD-associated HCC. This project is supported by Collaborative Research Fund (C4045–18W) and the AstraZeneca Preclinical Oncology Research Program (2017).