Fig. 8.

Endothelial cell anergy as a vascular immune checkpoint. Immune checkpoint molecules, such as PD-1 and PD-L1, dampen the activity of immune cells. A A tumor cell-specific CD8⁺ cytotoxic T-cell is prevented from its anti-tumor activity when immune checkpoint molecules are expressed on both cells. B Blocking these molecules by immune checkpoint inhibitory monoclonal antibodies unleashes the anti-tumor activity and cancer cells will be killed. C Angiogenic cancer cells, through secretion of angiogenic growth factors, can downregulate endothelial cell adhesion molecules that can make tumor endothelium unresponsive to proinflammatory cytokines. Such tumor EC anergy results in non-adhesive blood vessels and an immunologically silent tumor microenvironment. Immune suppression based on EC anergy is considered a vascular immune checkpoint. D Inhibition of angiogenesis through growth factor receptor blockade (with tyrosine kinase inhibitors) or neutralization of growth factors (with monoclonal antibodies) overcomes endothelial anergy making cancer cells vulnerable to immune cells. IFN, interferon; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; TCR, T-cell receptor; TNF, tumor necrosis factor. Figure is adapted from Huinen et al., 2021 [158]. Figure is created with BioRender.com and is available on request