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Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer

ABSTRACT: Maturation of conventional dendritic cells (cDCs) is crucial for maintaining tolerogenic safeguards against auto-immunity and for promoting immunogenic responses to pathogens and cancer. The subcellular mechanism for cDC maturation remains poorly defined. We show that cDCs mature by leveraging an internal reservoir of cholesterol – generated by de novo synthesis and recycled from extracellular cell debris – to assemble lipid nanodomains on cell surfaces of maturing cDCs, enhance expression of maturation markers, and stabilize immune receptor signaling. This process is dependent on cholesterol transport through Niemann-Pick disease type C1 (NPC1) and mediates homeostatic and TLR-induced maturation. Importantly, we identified the receptor tyrosine kinase AXL as a regulator of the NPC1-dependent construction of lipid nanodomains. Deleting AXL from cDCs enhances their maturation, thus improving antitumor immunity. Altogether, our study presents novel insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE282849 | GEO | 2025/02/03

REPOSITORIES: GEO

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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells snRNA-Seq

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