Tumor-Derived α-Fetoprotein Suppresses Fatty Acid Metabolism and Oxidative Phosphorylation in Dendritic Cells

Cellular metabolism supports immune cell function. Here, we identify a reduction in fatty acid synthesis and mitochondrial metabolism in dendritic cells (DC) due to alpha-fetoprotein (AFP), a protein secreted by hepatocellular cancer (HCC). DCs cultured in the presence of AFP show reduced expression of the metabolic regulatory molecules SREBP-1 and PGC1-alpha. The negative effect of AFP on mitochondrial metabolism and ATP production was confirmed with observation of reduction in basal oxygen consumption rate (OCR) in DCs exposed to AFP derived from cord blood. More severe reduction in basal OCR was observed in tumor-derived DCs exposed to AFP due to downregulation of cytochrome c oxidase. We also showed reduced expression of PGC1-alpha in circulating myeloid DCs of patients with HCC and impaired capacity to stimulate antigen-specific effector functions. These data show the negative effects of AFP on DC metabolism. These findings elucidate a mechanism of immune suppression in HCC and may help generate therapeutic approaches to reverse such immunosuppression.