[Immune therapy and tumor angiogenesis]

Angiogenesis is the process of new vascular formation from preexisting blood vessels, and the contribution of endothelial stem cell population to this process has been elucidated. Vascular endothelial growth factor (VEGF) promotes not only the proliferation of endothelial cells (ECs) but also the vascular permeability by inducing cell-to-cell dissociation between ECs. Chronic hyper vascular leakage induces intra-tumoral interstitial hypertension resulting in disturbed vascular perfusion. Hypoxia in the nonfunctional vasculatures causes chromosomal instability of cancer cells resulting in the development of malignant cancer cells, such as cancer stem cells. Hypoxia also induces exhaustion of immune cells. Moreover, the blood vessel structures in tumors are abnormal and nonfunctional, and the infiltration of leukocytes are suppressed. Moreover, drug delivery, including anti-cancer drugs and immune checkpoint inhibitors, is limited. A drug inducing normalization or maturation of abnormal blood vessels in tumor is warranted for the improvement of malignant tumor microenvironment.