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

Author

Listed:
  • 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
    Chinese Academy of Medical Sciences & Peking Union Medical College)

  • 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
    Lausanne University Hospital (CHUV)
    Ludwig Institute for Cancer Research)

  • Stéphanie Tissot

    (Swiss Cancer Center Leman
    Lausanne University Hospital (CHUV)
    Ludwig Institute for Cancer Research)

  • Jean-Marc Lobaccaro

    (BP38
    BP38
    58 Boulevard Montalembert)

  • Tatiana V. Petrova

    (Ludwig Institute for Cancer Research
    University of Lausanne)

  • Camilla Jandus

    (Department of Pathology and Immunology; Geneva Medical School
    Ludwig Institute for Cancer Research
    Geneva Centre for Inflammation Research
    Translational Research Centre in Oncohaematology)

  • 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
    Geneva Centre for Inflammation Research
    Translational Research Centre in Oncohaematology
    Ludwig-Maximilians-Universität Munich)

  • 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
    Geneva Centre for Inflammation Research
    Translational Research Centre in Oncohaematology)

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.

Suggested Citation

  • Mengzhu Sun & Laure Garnier & Romane Chevalier & Martin Roumain & Chen Wang & Julien Angelillo & Julien Montorfani & Robert Pick & Dale Brighouse & Nadine Fournier & David Tarussio & Stéphanie Tissot , 2025. "Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55969-w
    DOI: 10.1038/s41467-025-55969-w
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    References listed on IDEAS

    as
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