Tumor Vasculature as an Emerging Pharmacological Target to Promote Anti-Tumor Immunity

Abstract

Tumor vasculature abnormality creates a microenvironment that is not suitable for anti-tumor immune response and thereby induces resistance to immunotherapy. Remodeling of dysfunctional tumor blood vessels by anti-angiogenic approaches, known as vascular normalization, reshapes the tumor microenvironment toward an immune-favorable one and improves the effectiveness of immunotherapy. The tumor vasculature serves as a potential pharmacological target with the capacity of promoting an anti-tumor immune response. In this review, the molecular mechanisms involved in tumor vascular microenvironment-modulated immune reactions are summarized. In addition, the evidence of pre-clinical and clinical studies for the combined targeting of pro-angiogenic signaling and immune checkpoint molecules with therapeutic potential are highlighted. The heterogeneity of endothelial cells in tumors that regulate tissue-specific immune responses is also discussed. The crosstalk between tumor endothelial cells and immune cells in individual tissues is postulated to have a unique molecular signature and may be considered as a potential target for the development of new immunotherapeutic approaches.

Keywords: endothelial heterogeneity; immune response; immunotherapy; tumor angiogenesis; vasculature normalization.

Figure 1

Interactions between tumor endothelial cells (ECs) and immune populations to create the tumor immune microenvironment. Tumor blood vessel abnormalities results from an imbalance between pro- and anti-angiogenic signaling, which in turn results in a hypoxic and acidic TME. The hypoxia and acidosis regulate the immune response through pro-tumoral and anti-tumoral arms. The activation of endothelial cells can facilitate or inhibit tumor immunity through multiple pathways, including contact-dependent and soluble factor-mediated pathways. The blue arrows depict upregulation. The red lines show suppressive effects. MCT: Monocarboxylate transporter; HIF: Hypoxia-inducible factor; TAM: Tumor-associated macrophage; Treg: regulatory T cell; NK: natural killer; Ang-2: Angiopoietin 2; PSGL1: P-selectin glycoprotein ligand-1; VEGF: Vascular endothelial growth factor; VCAM: vascular cell adhesion protein; ICAM: Intercellular adhesion molecule; STAT3: Signal transducer and activator of transcription 3; NF-κB: Nuclear factor kappa-B; TCR: T cell receptor; HEVs: High endothelial venules; IFN-γ: Interferon-γ.

Figure 2

Immunomodulation of pro-angiogenic pathways and the approved drugs that target them. Triggering of VEGFR (mainly VEGFR2) pathways by the cognate ligands promotes CD8⁺ T cell exhaustion and apoptosis and inhibits their anti-tumor activity. Additionally, the immunosuppressive functions of TAMs and Foxp3⁺ Tregs are also induced. Tie2- and FGFR-mediated pathways activate pro-tumoral activity by recruiting TAMs/monocytes, which can further promote Treg-dependent tumor-supporting activity. The blue arrows depict activation. The red lines show inhibition. Bevacizumab and Aflibercept are VEGF inhibitory agents. Ramucirumab is the monoclonal antibody targeting VEGFR2. Axitinib, Sorafenib, Sunitinib, Nintedanib, and Regorafenib are tyrosine kinase inhibitors. Regorafenib and vandetanib are multi-kinase inhibitors that can inhibit Tie2-dependent signaling. TAM: tumor-associated macrophage; Treg: regulatory T cell; Ang-2: angiopoietin 2; VEGF: vascular endothelial growth factor; FGF: fibroblast growth factor; VEGFR: VEGF receptor; FGFR: FGF receptor; EC: endothelial cell.