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<p>Cutaneous melanomas express a high number of potential neoepitopes, yet a substantial fraction of melanomas shift into immunologically cold phenotypes. Using cellular systems, mouse models and large datasets, we identify the tumor-secreted growth factor midkine (MDK) as a multilayered inhibitor of antigen-presenting cells. Mechanistically, MDK acts systemically in primary tumors, lymph nodes and the bone marrow, promoting a STAT3-mediated impairment of differentiation, activation and function of dendritic cells (DCs), particularly, conventional type 1 DCs (cDC1s). Furthermore, MDK rewires DCs toward a tolerogenic state, impairing CD8<sup>+</sup> T cell activation. Downregulating MDK improves DC-targeted vaccination, CD40 agonist treatment and immune checkpoint blockade in mouse models. Moreover, we present an MDK-associated signature in DCs that defines poor prognosis and immune checkpoint blockade resistance in individuals with cancer. An inverse correlation between MDK- and cDC1-associated signatures was observed in a variety of tumor types, broadening the therapeutic implications of MDK in immune-refractory malignancies.</p>

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Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade

  • 期刊论文

  • 发表日期：

    2025年3月28日

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  • Xavier Catena,
  • Marta Contreras-Alcalde,
  • Naiara Juan-Larrea,
  • Daniela Cerezo-Wallis,
  • Tonantzin G. Calvo,
  • Cynthia Mucientes,
  • David Olmeda,
  • Javier Suárez,
  • Sergio Oterino-Sogo,
  • Lola Martínez,
  • Diego Megías,
  • David Sancho,
  • Cristina Tejedo,
  • Susana Frago,
  • Diana Dudziak,
  • Athanasios Seretis,
  • Patrizia Stoitzner,
  • María S. Soengas

摘要

Cutaneous melanomas express a high number of potential neoepitopes, yet a substantial fraction of melanomas shift into immunologically cold phenotypes. Using cellular systems, mouse models and large datasets, we identify the tumor-secreted growth factor midkine (MDK) as a multilayered inhibitor of antigen-presenting cells. Mechanistically, MDK acts systemically in primary tumors, lymph nodes and the bone marrow, promoting a STAT3-mediated impairment of differentiation, activation and function of dendritic cells (DCs), particularly, conventional type 1 DCs (cDC1s). Furthermore, MDK rewires DCs toward a tolerogenic state, impairing CD8+ T cell activation. Downregulating MDK improves DC-targeted vaccination, CD40 agonist treatment and immune checkpoint blockade in mouse models. Moreover, we present an MDK-associated signature in DCs that defines poor prognosis and immune checkpoint blockade resistance in individuals with cancer. An inverse correlation between MDK- and cDC1-associated signatures was observed in a variety of tumor types, broadening the therapeutic implications of MDK in immune-refractory malignancies.