Fig. 1

Rationale for combining VEGFR2 and PD-1/PD-L1 blockade. Tumor hypoxia leads to VEGFA/ANG induced disruptive tumor vascularization in a HIF-1a dependent manner. In turn, an immunosuppressive TME becomes established characterized by Treg, MDSCs, and M2 TAMs which inhibit CD4+ and CD8+ effector T cell mediated tumor immune response. In addition, the PD-1/PD-L1 axis is central in maintaining the immune suppressive TME by inhibiting CD4+ and CD8+ effector T cells. VEGFR2 blockade leads to tumor vessel normalization which potentiates PD1/PDL1 blockade by reversing established immune suppressive mechanisms. VEGFR2, vascular endothelial growth factor receptor 2; PD-1/L-1, programmed-death-1/ligand-1; ANG, angiopoietin; HIF-1a, hypoxia inducible factor-1a; Treg, regulatory T cell; MDSC, myeloid derived suppressor cell; TAM, tumor associated macrophages; DC, dendritic cells