Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma
Menée in vitro et à l'aide d'un modèle murin de glioblastome, cette étude met en évidence l'intérêt d'inhiber la kinase PAK4 pour normaliser la vascularisation du microenvironnement tumoral et améliorer l'efficacité des immunothérapies par lymphocytes CAR-T
Malignant solid tumors are characterized by aberrant vascularity that fuels the formation of an immune-hostile microenvironment and induces resistance to immunotherapy. Vascular abnormalities may be driven by pro-angiogenic pathway activation and genetic reprogramming in tumor endothelial cells (ECs). Here, our kinome-wide screening of mesenchymal-like transcriptional activation in human glioblastoma (GBM)-derived ECs identifies p21-activated kinase 4 (PAK4) as a selective regulator of genetic reprogramming and aberrant vascularization. PAK4 knockout induces adhesion protein re-expression in ECs, reduces vascular abnormalities, improves T cell infiltration and inhibits GBM growth in mice. Moreover, PAK4 inhibition normalizes the tumor vascular microenvironment and sensitizes GBM to chimeric antigen receptor–T cell immunotherapy. Finally, we reveal a MEF2D/ZEB1- and SLUG-mediated mechanism by which PAK4 reprograms the EC transcriptome and downregulates claudin-14 and VCAM-1 expression, enhancing vessel permeability and reducing T cell adhesion to the endothelium. Thus, targeting PAK4-mediated EC plasticity may offer a unique opportunity to recondition the vascular microenvironment and strengthen cancer immunotherapy.
Nature Cancer 2020