Journal Article

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

Mattiuz, Raphaël, Ghosh, Sourav, Blouin, Cédric M., Troncoso, Leanna, Marron, Thomas U., Reid, Amanda M., Amabile, Angelo, Azimi, Camillia S., Rothlin, Carla V., Boumelha, Jesse, Brown, Brian D., Radford, Kristen J., Yvan-Charvet, Laurent, Park, Matthew D., Quijada-Álamo, Miguel, Le Berichel, Jessica, Balan, Sreekumar, Peros, Ante, Bhardwaj, Nina, LaMarche, Nelson M., Freed, Grace, Chen, Steven T., Moon, Chang Y., Yatim, Nader, Merad, Miriam, Wilk, C. Matthias, Lamaze, Christophe, Wagenblast, Elvin, Belabed, Meriem, Puleston, Daniel J.

2025

Overview

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 (harnessed from extracellular cell debris and generated by de novo synthesis) 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 Toll-like receptor (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 anti-tumor immunity. Altogether, our study presents new insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs. To mature, dendritic cells collect and synthesize cholesterol to construct lipid nanodomains on their membranes. Obstructing this process impairs their ability to prime T cells.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/21/1566 / 631/250/2504/133/2505 / Animals / Axl protein / Axl Receptor Tyrosine Kinase / Biomedical and Life Sciences / Biomedicine / Cell Differentiation - immunology / Cholesterol / Cholesterol - metabolism / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - metabolism / Humans / Immunity / Immunogenicity / Immunology / Infectious Diseases / Lipids / Lymphocytes T / Maturation / Mice / Mice, Inbred C57BL / Mice, Knockout / Neoplasms - immunology / Niemann-Pick C1 Protein - metabolism / Niemann-Pick disease / Npc1 protein / Protein-tyrosine kinase receptors / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Receptor Protein-Tyrosine Kinases - genetics / Receptor Protein-Tyrosine Kinases - metabolism / Signal Transduction / Therapeutic targets / Toll-like receptors / Toll-Like Receptors - metabolism