TY - JOUR TI - Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma AU - Ma, Wenjuan AU - Wang, Yanling AU - Zhang, Rongxin AU - Yang, Fan AU - Zhang, Duo AU - Huang, Menggui AU - Zhang, Lin AU - Dorsey, Jay F. AU - Binder, Zev A. AU - O’Rourke, Donald M. AU - Fraietta, Joseph A. AU - Gong, Yanqing AU - Fan, Yi T2 - Nature Cancer AB - 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. DA - 2020/11/30/ PY - 2020 DO - 10.1038/s43018-020-00147-8 DP - www.nature.com SP - 1 EP - 15 LA - en SN - 2662-1347 UR - https://www.nature.com/articles/s43018-020-00147-8 Y2 - 2020/11/30/19:17:46 ER -