**5. VEGF immunomodulation**

Multiple possible mechanisms exist regarding immunosuppressive effects of VEGF on the tumour microenvironment. Firstly, due to the effect of VEGF on tumour vasculature, T cell migration from lymph nodes to the microenvironment may be impaired. Furthermore, the ability of T cells to migrate through vessels is negatively affected by VEGF through the down regulation of vascular endothelial selectins, adhesion molecules and promotion of Fas ligand expression. Secondly, VEGF binding to its receptor on myeloid derived suppressor cells within the tumour microenvironment results in STAT 3 signalling, with subsequent promotion of Treg cells and the down regulation of tumour specific T cells [18]. Additionally, the binding of VEGF to VEGFR2 has effects including reduced activation of cytotoxic CD8+ and CD4+ T cells, as well as the upregulation of inhibitory receptors including PD1 and CTLA4 [19]. The interaction of VEGF with VEGFR may also upregulate the programmed death ligand 1 (PDL1) on dendritic cells (DCs) [20]. Furthermore, the binding of VEGF to VEGFR1 on dendritic cells has the effect of inhibiting dendritic cell maturation [20].
