Inhibition of PAK2 in endothelial cells suppresses tumor angiogenesis and promotes immune sensitization through CXCL10
Tumor angiogenesis is driven by pro-angiogenic factors and results in a disorganized tumor vasculature that limits effective perfusion and immune infiltration. The p21-activated kinase 2 (PAK2) regulates endothelial cell (EC) migration, an essential step of angiogenesis, yet its role in tumor angiogenesis remains ill-defined. Here, we show that endothelial-specific deletion of PAK2 in orthotopic tumor mouse models markedly reduces tumor size and angiogenesis. Loss of endothelial PAK2 also normalizes the remaining tumor vasculature and promotes infiltration of dendritic and NK cells. Mechanistically, PAK2 regulates chemokine expression, notably CXCL10. PAK2 depletion enhances CXCL10 secretion from ECs, and CXCL10 expression is required for the inhibitory effects of PAK2 silencing on EC spouting. Moreover, CXCL10 neutralization in mice reverses the vascular and immune changes induced by endothelial PAK2 deletion. Together, these findings identify endothelial PAK2 as a potential target to limit tumor angiogenesis and reprogram ECs to promote immune infiltration through CXCL10 signaling. Overall design: RNA-seq of CT-PAK2EC and KO-PAK2EC LLC tumors in mice at day 18 of tumor growth. RNA-seq of siCT and siPAK2-transfected HUVEC, and RNA-seq of siCT, siPAK2, siCXCL10 and siPAK2-siCXCL10 transfected HUVEC