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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 (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.

Original languageEnglish
Article number94
Pages (from-to)188-199
Number of pages12
JournalNature Immunology
Volume26
Issue number2
DOIs
StatePublished - Feb 2025

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