Tumor Vasculatures: A New Target for Cancer Immunotherapy

Abstract

Immune cells rely on a functional vascular network to enter tissues. In solid tumors, blood vessels are abnormal and dysfunctional and, thus, immune effector cell infiltration is impaired. Although normalizing the tumor vasculature has been shown to improve the efficacy of cancer immunotherapies, recent studies suggest that enhanced immune stimulation also, in turn, improves tumor vascular normalization. Thus, this new paradigm of immune system-tumor vasculature mutual reprogramming opens the possibility of identifying new cancer treatment strategies that combine vascular targeting and immunotherapies. Here, we highlight current evidence supporting immune system-tumor vasculature crosstalk and outline how this relationship can provide new rationales for developing more effective combination immunotherapy strategies for treating human cancers.

Keywords: cancer immunotherapy; immune checkpoint blockade; tumor microenvironment; tumor vasculature; vascular normalization.

Figure 1.. Potential mechanism of immunotherapy-mediated tumor vascular normalization.

Activation of effector T cells in the setting of ICB results in production and secretion of IFNγ, which, through interaction with IFNγ receptors (IFNGR) expressed on vascular cells, results in normalization of the tumor vasculature. EC = endothelial cell.

Figure 2:. Immune or AT-mediated tumor vascular normalization improves tissue perfusion, leading to a decrease in tumor hypoxia and acidosis.

The reduced vascular permeability and leakiness also decreases interstitial fluid pressure (IFP) and thus helps to facilitate intratumoral delivery of chemo or targeted therapeutic agents. The increased oxygenation also enhances the production of reactive oxygen species (ROS), which further sensitizes solid tumors to definitive local treatments, such as targeted therapy or chemotherapy, as well as to ionizing radiation.