An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma

Menée à l'aide de modèles murins et d'échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, cette étude identifie une population de cellules endothéliales impliquées dans la polarisation des macrophages vers un profil immunosuppresseur et la résistance des cellules cancéreuses aux immunothérapies

Résumé en anglais

Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes. Genetic or pharmacological ablation of Twist1 reverses Mφ-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival, and sensitizing tumor to chimeric antigen receptor T immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling tumor immunity and suggest that targeting endothelial Twist1 may offer attractive opportunities for optimizing cancer immunotherapy. An immunosuppressive vascular niche educates macrophage immunity and drives tumor resistance to immunotherapy.