Inhibition of PAK2 in endothelial cells suppresses tumor angiogenesis and promotes immune sensitization through CXCL10

Abstract

Tumor angiogenesis is induced by the secretion of pro-angiogenic factors and results in a disorganized tumor vasculature. The p21-activated kinase 2 (PAK2) is involved in endothelial cell (EC) migration, an essential step of angiogenesis. However, the involvement of PAK2 in tumor angiogenesis remains ill-defined. Here, we show that, during orthotopic tumor growth, the specific deletion of PAK2 in ECs reduces tumor size and angiogenesis. In addition, endothelial-specific loss of PAK2 was found to normalize the remaining tumor blood vessels, favoring innate immune cells infiltration. Importantly, we uncovered a role for PAK2 in regulating chemokine expression, notably CXCL10. Secretion of CXCL10 from ECs is enhanced following PAK2 depletion and its expression is essential for the inhibitory effects of PAK2 silencing on EC spouting. Furthermore, neutralization of CXCL10 in mice reversed the effects induced by the deletion of PAK2 on tumor vasculature and immune composition of tumors. Together, our findings identify endothelial PAK2 as a potential target to reduce tumor angiogenesis and reprogram ECs to promote immune cell infiltration within tumors through the expression of CXCL10.