Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma
- 30 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 2 (1), 83-97
- https://doi.org/10.1038/s43018-020-00147-8
Abstract
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS094533, R01NS106108)
- American Association for Cancer Research (Judah Folkman Award)
- Penn | Perelman School of Medicine, University of Pennsylvania (RadOnc-TCE Award, Academic Development Fund, Abramson Cancer Center GBM-TCE Award, Abramson Cancer Center GBM-TCE Award)
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