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

Tumor angiogenesis is essential for the growth of solid tumors. This process is characterized by an increased secretion of pro-angiogenic factors and results in a disorganized tumor vasculature. It has been shown that the protein p21-activated kinase 2 (PAK2) is involved in the intracellular signaling cascades of pro-angiogenic factors leading to endothelial cell (EC) migration and lumen formation, all essential steps of physiological 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 tumor angiogenesis. In addition, endothelial-specific loss of PAK2 was found to normalize the remaining tumor blood vessels, favoring innate immune cells infiltration within tumors. Importantly, we uncovered a role for PAK2 in regulating chemokine expression, notably C-X-C motif chemokine 10 (CXCL10). Secretion of CXCL10 is enhanced following PAK2 depletion in ECs. Furthermore, we show that CXCL10 is essential for the effects induced by the deletion of PAK2 on tumor vasculature and immune composition of tumors. Together, our findings identify PAK2 inhibition in tumor ECs as a potential target to reduce tumor angiogenesis and reprogram ECs to promote immune cell infiltration within tumors through the expression of CXCL10.