Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma

Mengzhu Sun, Laure Garnier, Romane Chevalier, Martin Roumain, Chen Wang, Julien Angelillo, Julien Montorfani, Robert Pick, Dale Brighouse, Nadine Fournier, David Tarussio, Stéphanie Tissot, Jean-Marc Lobaccaro, Tatiana V. Petrova, Camilla Jandus, Daniel E. Speiser, Manfred Kopf, Caroline Pot, Christoph Scheiermann, Krisztian Homicsko, Giulio G. Muccioli, Abhishek D. Garg and Stéphanie Hugues ()
Additional contact information
Mengzhu Sun: Department of Pathology and Immunology; Geneva Medical School
Laure Garnier: Department of Pathology and Immunology; Geneva Medical School
Romane Chevalier: Department of Pathology and Immunology; Geneva Medical School
Martin Roumain: Université catholique de Louvain
Chen Wang: Department of Pathology and Immunology; Geneva Medical School
Julien Angelillo: Department of Pathology and Immunology; Geneva Medical School
Julien Montorfani: Department of Pathology and Immunology; Geneva Medical School
Robert Pick: Department of Pathology and Immunology; Geneva Medical School
Dale Brighouse: Department of Pathology and Immunology; Geneva Medical School
Nadine Fournier: Swiss Institute of Bioinformatics (SIB)
David Tarussio: Swiss Cancer Center Leman
Stéphanie Tissot: Swiss Cancer Center Leman
Jean-Marc Lobaccaro: BP38
Tatiana V. Petrova: Ludwig Institute for Cancer Research
Camilla Jandus: Department of Pathology and Immunology; Geneva Medical School
Daniel E. Speiser: University of Lausanne
Manfred Kopf: Swiss Federal Institute of Technology (ETH)
Caroline Pot: Lausanne University Hospital and University of Lausanne
Christoph Scheiermann: Department of Pathology and Immunology; Geneva Medical School
Krisztian Homicsko: University of Lausanne
Giulio G. Muccioli: Université catholique de Louvain
Abhishek D. Garg: Department of Cellular & Molecular Medicine (CMM)
Stéphanie Hugues: Department of Pathology and Immunology; Geneva Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract In melanoma, lymphangiogenesis correlates with metastasis and poor prognosis and promotes immunosuppression. However, it also potentiates immunotherapy by supporting immune cell trafficking. We show in a lymphangiogenic murine melanoma that lymphatic endothelial cells (LECs) upregulate the enzyme Ch25h, which catalyzes the formation of 25-hydroxycholesterol (25-HC) from cholesterol and plays important roles in lipid metabolism, gene regulation, and immune activation. We identify a role for LECs as a source of extracellular 25-HC in tumors inhibiting PPAR-γ in intra-tumoral macrophages and monocytes, preventing their immunosuppressive function and instead promoting their conversion into proinflammatory myeloid cells that support effector T cell functions. In human melanoma, LECs also upregulate Ch25h, and its expression correlates with the lymphatic vessel signature, infiltration of pro-inflammatory macrophages, better patient survival, and better response to immunotherapy. We identify here in mechanistic detail an important LEC function that supports anti-tumor immunity, which can be therapeutically exploited in combination with immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-55969-w

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