PD1 blockade-induced DKK1 expression by CD8+ T cells promotes blood-brain barrier permeabilization
Menée à l'aide de lignées cellulaires, de modèles murins de tumeur et d'IRM 3D FLAIR réalisées sur des patients atteints d'un cancer du poumon, cette étude met en évidence un mécanisme par lequel les anti-PD1 favorisent la perméabilisation de la barrière hémato-encéphalique en augmentant l'expression de la protéine DKK1 par les lymphocytes T CD8+
Anti-PD1 therapy benefits a subset of brain metastasis (BrM) patients; however, heterogeneous responses imply an incomplete understanding of the brain-immune ecosystem. To elucidate host-driven determinants of this variability, we performed single-cell RNA sequencing to characterize the brain microenvironment. While anti-PD1 induced robust anti-tumor immune activation, it uniquely, among all ICIs tested, compromised blood-brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8⁺ T cells through the induction of β-catenin/TCF and FOXM1 pathways, contributing to endothelial cell destabilization. Depleting plasma-DKK1 restored BBB integrity and reduced experimental BrM formation. Clinically, lung cancer patients receiving anti-PD1 exhibited increased MRI contrast enhancement in the brain, suggestive of BBB perturbations, and increasing plasma DKK1 levels correlated with higher BrM incidence in non-responders. Sequencing anti-PD1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD1-induced BBB modulation as a tractable vulnerability in BrM management.
Cancer Discovery , article en libre accès, 2026