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

Article Article scientifique Article Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma eng 2025-01-31 2025-01-31 author Sun Mengzhu 0009-0004-5561-9334 Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. 919193 author Garnier Laure Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. 878285 Département de pathologie et immunologie (PATIM) author Chevalier Romane Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. 923517 author Roumain Martin Metabolism and Nutrition Research Group, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. author Wang Chen 0000-0003-2271-5587 Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland.,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. 894272 author Angelillo Julien Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. 781372 author Montorfani Julien Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. 821829 author Pick Robert 0000-0001-9785-8481 Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. 921203 Département de pathologie et immunologie (PATIM) author Brighouse Dale Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. 134767 Département de pathologie et immunologie (PATIM) author Fournier Nadine 0000-0002-9347-7929 Translational Data Science (TDS), Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. 982766 Services communs de la faculté de médecine (SCMU) author Tarussio David Swiss Cancer Center Leman, Lausanne, Switzerland.,Department of Oncology, Center for Experimental Therapeutics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Tissot Stéphanie 0000-0003-3080-4598 Swiss Cancer Center Leman, Lausanne, Switzerland.,Department of Oncology, Center for Experimental Therapeutics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Lobaccaro Jean-Marc 0000-0001-9890-2392 Université Clermont Auvergne, iGReD, CNRS UMR 6293, INSERM U1103, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France.,Groupe Cancer Clermont Auvergne, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, 58 Boulevard Montalembert, F-63009, Clermont-Ferrand, France. author Petrova Tatiana V 0000-0002-0563-6521 Ludwig Institute for Cancer Research, Lausanne, Switzerland.,Department of Oncology, University of Lausanne, Lausanne, Switzerland. author Jandus Camilla 0000-0002-7405-5747 Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland.,Geneva Centre for Inflammation Research, Geneva, Switzerland.,Translational Research Centre in Oncohaematology, Geneva, Switzerland. 932821 Département de pathologie et immunologie (PATIM) author Speiser Daniel E 0000-0003-2031-3250 Department of Oncology, University of Lausanne, Lausanne, Switzerland. author Kopf Manfred Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland. author Pot Caroline 0000-0002-1146-3129 Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Scheiermann Christoph 0000-0002-9212-0995 Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland.,Geneva Centre for Inflammation Research, Geneva, Switzerland.,Translational Research Centre in Oncohaematology, Geneva, Switzerland.,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. 891044 Département de pathologie et immunologie (PATIM) author Homicsko Krisztian Department of Oncology, University of Lausanne, Lausanne, Switzerland. author Muccioli Giulio G 0000-0002-1600-9259 Metabolism and Nutrition Research Group, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. author Garg Abhishek D 0000-0002-9976-9922 Laboratory for Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine (CMM), KU Leuven, Belgium. author Hugues Stéphanie Department of Pathology and Immunology; Geneva Medical School, Geneva, Switzerland. stephanie.hugues@unige.ch.,Geneva Centre for Inflammation Research, Geneva, Switzerland. stephanie.hugues@unige.ch.,Translational Research Centre in Oncohaematology, Geneva, Switzerland. stephanie.hugues@unige.ch. 663452 Département de pathologie et immunologie (PATIM) 1217 10.1038/s41467-025-55969-w 39890772 2041-1723 PMC11893137 https://www.nature.com/articles/s41467-025-55969-w 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. Animals Humans Immunotherapy / methods Mice Melanoma / immunology Melanoma / therapy Melanoma / pathology Melanoma / metabolism Endothelial Cells / metabolism Endothelial Cells / immunology Hydroxycholesterols / metabolism Macrophages / immunology Macrophages / metabolism Steroid Hydroxylases / metabolism Steroid Hydroxylases / genetics Cell Line, Tumor Lymphatic Vessels / metabolism Lymphatic Vessels / immunology Oxysterols / metabolism Oxysterols / immunology Female Mice, Inbred C57BL Lymphangiogenesis / immunology Dewey 616.07 Swiss National Science Foundation Role of lymphatic endothelial cells in Autoimmunity and Cancer 185255 CH Swiss National Science Foundation Lymphatic vessels as immunomodulators in Autoimmunity and Cancer 215017 CH 137 Département de pathologie et immunologie 21F false 1259 L'influence du rôle du cycle circadien sur l'immunité 995 563 Pathologie et immunologie 906 1309 Ciblage des lymphocytes sécrétant des cytokines 1015 0a6434c9-7972-44ea-8708-82e501660dc7 Biomedical Data Science Facility https://yareta.unige.ch/archives/5cf27f25-e488-465f-8a67-228ac082ab91 Nature communications 16 1 ec1e9043-d46a-4a33-8e30-7aa5c3f5ed30 Article (Published version) Public Article_scientifique_from_europePmc.pdf 3912390 application/pdf CC BY-NC-ND-4.0 64e3b83cae8ad4f217857730543f60cbd59b18edd05bb067fe2e34c51a0bdd8f dac26528-c7a4-4242-8eda-5ff774284ed2 Appendix Public 41467_2025_55969_MOESM1_ESM.pdf 10084308 application/pdf 0f856e1c1878a7c082805825be87ea8ac681fbbe54d0dbb1395ff7d9e5117d43 c75f83a4-7091-4477-b3eb-05d97f1a558a Appendix Public 41467_2025_55969_MOESM2_ESM.pdf 1643293 application/pdf 077ce024e9706e273ba8ae2c9cdf4ba6c5ef5c4ff847563376e572d26ddb117c c7d65678-3db7-464a-be20-45221d45e7f8 Appendix Public 41467_2025_55969_MOESM3_ESM.pdf 2522051 application/pdf 16e591b563fa6f4050ba463b5433e62dabf769b8ca828dc6535fb1db70b11ccf ab857c32-3d87-4d22-857c-361591d6267c Appendix Public 41467_2025_55969_MOESM4_ESM.zip 61686673 application/zip 529d0cb75dbab5d03c0d15f3671790cc6f0259e230827223496633797d2b7fec openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma	Nature communications			2025	86	28

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