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 Brown; Kristen J Radford; Sourav Ghosh; Carla V Rothlin; Laurent Yvan-Charvet; Thomas U Marron; Daniel J Puleston; Elvin Wagenblast; Nina Bhardwaj; Christophe Lamaze; Miriam Merad

doi:10.1038/s41590-024-02065-8

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

Nat Immunol. 2025 Jan 21. doi: 10.1038/s41590-024-02065-8. Online ahead of print.

Authors

Meriem Belabed^#^{1

2

3}, Matthew D Park^#^{1

2

3}, Cédric M Blouin^{4

5

6}, Sreekumar Balan^{1

2

3}, Chang Y Moon^{1

2

3}, Grace Freed², Miguel Quijada-Álamo², Ante Peros^{1

2

3}, Raphaël Mattiuz^{1

2

3}, Amanda M Reid^{1

2

3}, Nader Yatim^{1

2

3}, Jesse Boumelha^{1

2

3}, Camillia S Azimi^{1

2

3}, Nelson M LaMarche^{1

2

3}, Leanna Troncoso^{1

2

3}, Angelo Amabile^{1

2

3}, Jessica Le Berichel^{1

2

3}, Steven T Chen^{1

2

3}, C Matthias Wilk^{1

2

3}, Brian D Brown^{1

2

3}, Kristen J Radford⁷, Sourav Ghosh⁸, Carla V Rothlin⁹, Laurent Yvan-Charvet¹⁰, Thomas U Marron^{1

2

3

11

12}, Daniel J Puleston^{1

2

3}, Elvin Wagenblast², Nina Bhardwaj^{1

2

3}, Christophe Lamaze^{4

5

6}, Miriam Merad^{13

14

15}

Affiliations

¹ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Membrane Mechanics and Dynamics of Intracellular Signaling Laboratory, Centre de Recherche, Institut Curie, PSL Research University, Paris, France.
⁵ Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
⁶ Centre National de la Recherche Scientifique, Paris, France.
⁷ Mater Research Institute, the University of Queensland, Brisbane, Queensland, Australia.
⁸ Department of Immunobiology and Department of Pharmacology, Yale School of Medicine, Yale University, New Haven, CT, USA.
⁹ Department of Neurology and Department of Pharmacology, Yale School of Medicine, Yale University, New Haven, CT, USA.
¹⁰ INSERM U1065, ATIP-Avenir, Fédération Hospitalo-Universitaire OncoAge, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.
¹¹ Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
¹⁴ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
¹⁵ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].

^# Contributed equally.

PMID: 39838105
DOI: 10.1038/s41590-024-02065-8

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.

Abstract

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