2. Academic Validation
  3. Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma

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

  • Nat Commun. 2025 Jan 31;16(1):1217. doi: 10.1038/s41467-025-55969-w.
Mengzhu Sun 1,  Laure Garnier 1,  Romane Chevalier 1,  Martin Roumain 2,  Chen Wang 1 3,  Julien Angelillo 1,  Julien Montorfani 1,  Robert Pick 1,  Dale Brighouse 1,  Nadine Fournier 4,  David Tarussio 5 6 7,  Stéphanie Tissot 5 6 7,  Jean-Marc Lobaccaro 8 9 10,  Tatiana V Petrova 7 11,  Camilla Jandus 1 7 12 13,  Daniel E Speiser 11,  Manfred Kopf 14,  Caroline Pot 15,  Christoph Scheiermann 1 12 13 16,  Krisztian Homicsko 11,  Giulio G Muccioli 2,  Abhishek D Garg 17,  Stéphanie Hugues 18 19 20
Affiliations

Affiliations

  • 1 Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland.
  • 2 Metabolism and Nutrition Research Group, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
  • 3 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China.
  • 4 Translational Data Science (TDS), Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
  • 5 Swiss Cancer Center Leman, Lausanne, Switzerland.
  • 6 Department of Oncology, Center for Experimental Therapeutics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
  • 7 Ludwig Institute for Cancer Research, Lausanne, Switzerland.
  • 8 Université Clermont Auvergne, iGReD, CNRS UMR 6293, INSERM U1103, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France.
  • 9 Groupe Cancer Clermont Auvergne, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France.
  • 10 Centre de Recherche en Nutrition Humaine d'Auvergne, 58 Boulevard Montalembert, F-63009, Clermont-Ferrand, France.
  • 11 Department of Oncology, University of Lausanne, Lausanne, Switzerland.
  • 12 Geneva Centre for Inflammation Research, Geneva, Switzerland.
  • 13 Translational Research Centre in Oncohaematology, Geneva, Switzerland.
  • 14 Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.
  • 15 Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • 16 Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter-Brendel-Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Planegg-Martinsried, Germany.
  • 17 Laboratory for Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine (CMM), KU Leuven, Belgium.
  • 18 Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. stephanie.hugues@unige.ch.
  • 19 Geneva Centre for Inflammation Research, Geneva, Switzerland. stephanie.hugues@unige.ch.
  • 20 Translational Research Centre in Oncohaematology, Geneva, Switzerland. stephanie.hugues@unige.ch.
PMID: 39890772 DOI: 10.1038/s41467-025-55969-w
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.

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