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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月31日

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  • 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

摘要

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.