Polyunsaturated fatty acid-bound alpha-fetoprotein promotes immune suppression by altering human dendritic cell metabolism.

Alpha-fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell differentiation and maturation and to block oxidative phosphorylation. To identify the critical metabolic pathways leading to human dendritic cell functional suppression, here we utilized two recently described single cell profiling methods, scMEP (single-cell metabolic profiling) and SCENITH (single-cell energetic metabolism by profiling translation inhibition). Glycolytic capacity and glucose dependence of dendritic cells was significantly increased by tumor-derived, but not normal cord blood-derived, AFP, leading to increased glucose uptake and lactate secretion. Key molecules in the electron transport chain in particular were regulated by tumor-derived AFP. These metabolic changes occurred at mRNA and protein levels, with negative impact on dendritic cell stimulatory capacity. Tumor-derived AFP bound significantly more polyunsaturated fatty acids than cord blood-derived AFP. Polyunsaturated fatty acids bound to AFP increased metabolic skewing and promoted dendritic cell functional suppression. Polyunsaturated fatty acids inhibited dendritic cell differentiation in vitro, and ω-6 polyunsaturated fatty acids conferred potent immunoregulation when bound to tumor-derived AFP. Together, these findings provide mechanistic insights into how AFP antagonizes the innate immune response to limit anti-tumor immunity.