Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma
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| Title: | Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma |
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| Authors: | 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 |
| Contributors: | UCL - SSS/LDRI - Louvain Drug Research Institute |
| Source: | Nat Commun Nature Communications, Vol 16, Iss 1, Pp 1-22 (2025) Nature Communications, Vol. 16, no.1 (2025) Nature communications, vol. 16, no. 1, pp. 1217 |
| Publisher Information: | Springer Science and Business Media LLC, 2025. |
| Publication Year: | 2025 |
| Subject Terms: | EXPRESSION, Male, Science, Animals, Humans, Immunotherapy/methods, Melanoma/immunology, Melanoma/therapy, Mice, Hydroxycholesterols/metabolism, Endothelial Cells/immunology, Endothelial Cells/metabolism, Mice, Inbred C57BL, Oxysterols/metabolism, Cell Line, Tumor, Lymphangiogenesis/drug effects, Lymphatic Vessels/immunology, Lymphatic Vessels/pathology, Macrophages/immunology, Macrophages/metabolism, Female, Melanoma, Experimental/immunology, Melanoma, Experimental/therapy, Steroid Hydroxylases, Melanoma, Experimental, CELL-MIGRATION, Article, ACTIVATION, TUMOR, REVEALS, MACROPHAGES, Lymphangiogenesis, Melanoma, Lymphatic Vessels, Science & Technology, Macrophages, Endothelial Cells, Oxysterols, Hydroxycholesterols, Multidisciplinary Sciences, RECEPTORS, MONOCYTES, Science & Technology - Other Topics, PPAR-GAMMA, Immunotherapy, LYMPHANGIOGENESIS |
| Description: | 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. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-55969-w |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/39890772 https://doaj.org/article/0af122abda854646bb7ed8b7aa8c081f https://hdl.handle.net/2078.1/303168 https://serval.unil.ch/notice/serval:BIB_BADF9D7710DC https://serval.unil.ch/resource/serval:BIB_BADF9D7710DC.P001/REF.pdf http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_BADF9D7710DC6 |
| Rights: | CC BY NC ND |
| Accession Number: | edsair.doi.dedup.....266071ebeaf6a2371a97a3831bd08e4f |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | 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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| ISSN: | 20411723 |
| DOI: | 10.1038/s41467-025-55969-w |