Vascular regulation of antitumor immunity

Abstract

Blood and lymphatic vessels regulate antitumor immunity through direct and indirect mechanisms, providing new opportunities for improving cancer immunotherapy.

Excess angiogenic molecules produced by cancer or host cells cause abnormal tumor vasculature. Aberrant ECM deposition by CAFs and uncontrolled tumor growth create mechanical stresses that compress blood vessels, limiting blood perfusion and the delivery of immune cells, oxygen and immunotherapy drugs to the cancer cells. The abnormal, hypoxic and fibrotic microenvironment further upregulates angiogenic molecules such as VEGF, altering endothelial barrier function and adhesion molecules. The abnormal TME also upregulates immune checkpoint molecules such as PD-L1. These alterations further limit the activity of effector T cells, while recruiting immunosuppressive innate immune cells such as MDSCs and reprogramming anti-tumor TAMs to pro-tumor phenotype. Anti-fibrotic drugs can decompress the blood vessels and anti-angiogenesis therapies can reverse many of the TME abnormalities, resulting in improved perfusion, less hypoxia, better immune cell infiltration and creation of an immunostimulatory microenvironment.