Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade
Menée à l'aide de lignées cellulaires, de modèles murins de mélanome cutané et de plusieurs séries de données, cette étude met en évidence un mécanisme par lequel la sécrétion de la midkine par les cellules cancéreuses entrave la surveillance immunitaire et la réponse aux inhibiteurs de point de contrôle immunitaire en agissant sur la différenciation, l'activation et la fonction des cellules dendritiques
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.
Nature Cancer , résumé, 2025