Polyunsaturated Fatty Acid-Bound α-Fetoprotein Promotes Immune Suppression by Altering Human Dendritic Cell...

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Research

Background:

• Alpha-fetoprotein (AFP) is a tumor biomarker linked to poor prognosis in hepatocellular carcinoma.
• AFP inhibits dendritic cell (DC) maturation and blocks oxidative phosphorylation, crucial for immune response.
• Understanding AFP's metabolic effects on DCs is vital for developing cancer immunotherapies.

Purpose of the Study:

• To identify metabolic pathways responsible for AFP-induced human DC functional suppression.
• To investigate the role of tumor-derived AFP in altering DC metabolism and function.
• To explore the impact of fatty acid binding on AFP's immunomodulatory effects.

Main Methods:

• Utilized single-cell metabolic profiling (scMEP) and SCENITH to analyze DC metabolism.
• Compared metabolic profiles of DCs treated with tumor-derived AFP versus normal cord blood-derived AFP.
• Assessed the impact of polyunsaturated fatty acids (PUFAs) bound to AFP on DC function in vitro.

Main Results:

• Tumor-derived AFP significantly increased DC glycolytic capacity and glucose uptake, leading to lactate secretion.
• AFP altered key molecules in the electron transport chain, affecting DC energetics at mRNA and protein levels.
• AFP bound more polyunsaturated fatty acids (PUFAs), particularly ω-6 PUFAs, which exacerbated metabolic skewing and DC suppression.

Conclusions:

• Tumor-derived AFP actively suppresses innate immune responses by reprogramming DC metabolism toward glycolysis.
• Fatty acid binding, especially PUFAs, potentiates AFP's immune-suppressive function.
• These findings offer mechanistic insights into how AFP limits antitumor immunity, suggesting potential therapeutic targets.