Immune cell infiltration into brain tumor microenvironment is mediated by Rab27-regulated vascular wall integrity
Menée à l'aide de lignées cellulaires et de modèles murins de tumeur cérébrale, cette étude met en évidence le rôle des protéines Rab27a/b dans le contrôle de l'intégrité vasculaire et de l'infiltration des cellules immunitaires dans le microenvironnement tumoral
Aggressive brain tumors often exhibit immunologically ‘cold’ microenvironment, where the vascular barrier impedes effective immunotherapy in poorly understood ways. Tumor vasculature also plays a pivotal role in immunoregulation and antitumor immunity. Here, we show that small GTPase Rab27 controls the vascular morphogenesis and permeability for blood content and immune effectors. Thus, in Rab27a/b double knock out (Rab27-dKO) mice, the brain vasculature is abnormally scarce, while the blood vessels become dysmorphic and hyperpermeable in the context of brain tumors, including syngeneic glioblastoma. These defects are reflected in rearrangements of endothelial cell subpopulations with underlying diminution of venous endothelial subtype along with changes in gene and protein expression. Notably, Rab27-dKO brain endothelial cells exhibit deficient tight junctions, whereby they enable large-scale extravasation of cytotoxic T cells into the tumor mass. We show that Rab27-regulated vascular T cell infiltration can be exploited to enhance adoptive T cell therapy in syngeneic brain tumors. The vascular barrier in brain cancer can be disrupted by targeting Rab27 to allow immune cell passage and immunotherapy.
Science Advances , article en libre accès, 2025