CD4⁺ T Cell Loss Drives NAFLD Progression to Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) has been linked to chronic inflammation and metabolic deregulation and often arises in patients with nonalcoholic fatty liver disease (NAFLD). Although immune evasion has been implicated in HCC initiation and progression, the role of the adaptive immune response in NAFLD-driven HCC remains unclear. To address this, Ma and colleagues used murine models of HCC and NAFLD and found that NAFLD accelerated HCC and led to a liver-specific depletion and activation of CD4⁺ T lymphocytes. Antibody-mediated depletion of CD4⁺ T cells promoted HCC tumorigenesis. Characterization of hepatocytic CD4⁺ T cells from HCC/NAFLD mice revealed high levels of apoptosis associated with increased levels of linoleic acid. Treatment of CD4⁺ T cells with exogenous linoleic acid promoted apoptosis, while depletion of free fatty acids (FFA) from culture media prevented CD4⁺ T cell death. CD4⁺ T cells harbored increased mitochondrial mass, and in response to linoleic acid exhibited elevated expression of CPT1A, a rate-limiting enzyme involved in FFA mitochondrial import, and defects in electron transport activity and mitochondrial membrane potential, suggesting that altered FFA processing within the mitochondria may be linked to apoptosis. Consistent with these findings, shRNA knockdown of CPT1A rescued linoleic acid–induced CD4⁺ T cell death. Exogenous linoleic acid treatment promoted a shift in oxygen consumption towards ATP-synthase-independent reactive oxygen species (ROS) production. Increased ROS was observed in CD4⁺ T cells after linoleic acid treatment, and suppression of ROS inhibited linoleic acid–mediated CD4⁺ T cell death in vitro and delayed hepatocytic tumor formation in vivo. Exogenous linoleic acid treatment was also shown to drive ROS production and apoptosis in human CD4⁺ T cell populations, and fewer CD4⁺ T cells were observed in patients with non–viral-associated hepatitis. Together, these data suggest that NAFLD-associated lipid disruption promotes tumorigenesis as a result of ROS-induced CD4⁺ T cell depletion.

Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4⁺ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016;531:253–257.