Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma
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...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55969-w |
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| author | 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 Stéphanie Hugues |
| author_facet | 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 Stéphanie Hugues |
| author_sort | Mengzhu Sun |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0af122abda854646bb7ed8b7aa8c081f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0af122abda854646bb7ed8b7aa8c081f2025-02-02T12:31:12ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-025-55969-wLymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanomaMengzhu Sun0Laure Garnier1Romane Chevalier2Martin Roumain3Chen Wang4Julien Angelillo5Julien Montorfani6Robert Pick7Dale Brighouse8Nadine Fournier9David Tarussio10Stéphanie Tissot11Jean-Marc Lobaccaro12Tatiana V. Petrova13Camilla Jandus14Daniel E. Speiser15Manfred Kopf16Caroline Pot17Christoph Scheiermann18Krisztian Homicsko19Giulio G. Muccioli20Abhishek D. Garg21Stéphanie Hugues22Department of Pathology and Immunology; Geneva Medical SchoolDepartment of Pathology and Immunology; Geneva Medical SchoolDepartment of Pathology and Immunology; Geneva Medical SchoolMetabolism and Nutrition Research Group, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université catholique de LouvainDepartment of Pathology and Immunology; Geneva Medical SchoolDepartment of Pathology and Immunology; Geneva Medical SchoolDepartment of Pathology and Immunology; Geneva Medical SchoolDepartment of Pathology and Immunology; Geneva Medical SchoolDepartment of Pathology and Immunology; Geneva Medical SchoolTranslational Data Science (TDS), Swiss Institute of Bioinformatics (SIB)Swiss Cancer Center LemanSwiss Cancer Center LemanUniversité Clermont Auvergne, iGReD, CNRS UMR 6293, INSERM U1103, 28, place Henri Dunant, BP38Ludwig Institute for Cancer ResearchDepartment of Pathology and Immunology; Geneva Medical SchoolDepartment of Oncology, University of LausanneInstitute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH)Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of LausanneDepartment of Pathology and Immunology; Geneva Medical SchoolDepartment of Oncology, University of LausanneMetabolism and Nutrition Research Group, Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université catholique de LouvainLaboratory for Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine (CMM)Department of Pathology and Immunology; Geneva Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-025-55969-w |
| spellingShingle | 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 Stéphanie Hugues Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma Nature Communications |
| title | Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma |
| title_full | Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma |
| title_fullStr | Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma |
| title_full_unstemmed | Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma |
| title_short | Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma |
| title_sort | lymphatic derived oxysterols promote anti tumor immunity and response to immunotherapy in melanoma |
| url | https://doi.org/10.1038/s41467-025-55969-w |
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