Fig. 1
From: Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment
Tumor angiogenesis induces the formation of immunosuppressive tumor microenvironment. Firstly, leaky nascent vessels and loose pericyte coverage result in high interstitial fluid pressure (IFP) which means greater pressure difference to overcome for T cell infiltration. Secondly, neo-vasculatures tend to lack some adhesion molecules for example vasculature cell adhesion molecule-1 (VCAM-1). Thirdly, hypoxia upregulates some inhibitory signals for anti-tumor immune response such as PD-L1, indoleamine 2, 3-dioxygenase (IDO), interleukin-6 (IL-6), and interleukin-10 (IL-10) . In addition, circulating VEGF impedes the maturation and function of dendritic cell (DC). Besides, tumor hypoxia induces upregulation of chemokine (C-C motif) ligand-22 and chemokine (C-C motif) ligand-28, which recruit Treg into tumor [36, 37]. Moreover, hypoxic tumor microenvironment promotes the polarization of tumor-associated macrophage (TAM) to M2-like phenotype. Lastly, the expression of Fas ligand (FasL) on tumor endothelial barrier selectively eliminates effector CD8+ T cells rather than Treg, due to the high expression of cellular FLICE-inhibitory protein (c-FLIP) expression on Treg. In summary, angiogenesis render accumulating pro-tumor immune cells and decreasing anti-tumor immune cells, inducing the formation of immunosuppressive tumor microenvironment