Fig. 3
From: Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment
Mutual regulation of tumor vessel normalization and immune microenvironment reprogramming. Tumor angiogenesis leads to an immunosuppressive microenvironment by decreasing the ratio of anti-tumor/pro-tumor immune cell and undermining the function of cytotoxic T lymphocyte (CTL). Anti-angiogenesis induces tumor vessel normalization and improves blood perfusion. Alleviated hypoxia decreases PD-L1 expression on tumor cell while blocked VEGF signal downregulates immune checkpoint expression (e.g. PD-1) on CTL. In the meanwhile, activated immune response-derived inflammatory factors such as interferon-γ (IFN-γ) promotes vessel normalization and regression. Interaction between vessel normalization and immune microenvironment reprogramming could be regulated by anti-angiogenesis agents (bevacizumab or VEGFR-TKI such as axitinib, sorafenib, sunitinib, and vatalanib) and ICI (especially anti-PD-1/PD-L1 mAb). After combination therapy, immunosuppressive microenvironment is transformed to immunosupportive microenvironment which possesses increased CTL, M1-like phonotype macrophage, adhesion molecule, mature dendritic cell (DC), and decreased regulatory T cell (Treg). Abbreviations: TAM, tumor associated macrophage; EC, endothelial cell