NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis

Abstract

Summary Hepatocellular carcinoma (HCC) is the second most common cause of cancer related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered a metabolic predisposition to liver cancer 1-5. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here, we show that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes leading to accelerated hepatocarcinogenesis. We also found that CD4+ T lymphocytes have greater mitochondrial mass than CD8+ T lymphocytes and generate higher levels of mitochondrially-derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4+ T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4+ T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumor surveillance.

Foxp3 drives oxidative phosphorylation and protection from lipotoxicity

“…Dysregulation of lipid metabolism can lead to tissue-specific inflammatory pathology. Nonalcoholic fatty liver disease has been shown to result in release of linoleic acid (C18:2) from hepatocytes, leading to preferential CD4 + T cell apoptosis via increased ROS production and decreased Δψm (56). Saturated fat has also been shown to potently activate innate immunity in mice with macrophages lacking a regulator of lipoprotein lipase, Angiopoietin-like protein 4 (Angptl4).…”

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

“…In concert with chronic compensatory hepatocyte regeneration and proliferation-induced mutagenesis, chronic ROS exposure sets the stage for HCC development. Key mechanisms include ROS-mediated DNA damage and genomic instability in hepatocytes (21), as well as inhibitory effects on T lymphocyte-mediated tumor immunosurveillance (22). Accordingly, inhibition of ROS formation by the antioxidants butylated hydroxyanisole or N-acetylcysteine results in a strong suppression of experimental hepatocarcinogenesis (23, 24).…”

“…As such, activated and proliferating HSCs have been shown to switch monocytes from inflammatory to an immunosuppressive and tumor-promoting M2 phenotype, thus allowing immune evasion by developing tumors (53, 75). In NAFLD, there is a failure of CD4+ T cell-mediated immunosuppression, mediated by linoleic acid-induced mitochondrial ROS generation and subsequent loss of CD4+ T cells, resulting in increased hepatocarcinogenesis (22). …”

Immunotherapy of Hepatocellular Carcinoma

“…Importantly, as a result of distinct molecular changes within the hepatic microenvironment, the response to immunotherapy can be significantly influenced by the underlying liver disease [24,25]. These context-dependent changes have to be considered and critically evaluated when immune-therapeutic interventions are applied to HCC patients [26].…”