Vascular Endothelial Growth Factor (VEGF) Family and the Immune System: Activators or Inhibitors?

Abstract

The vascular endothelial growth factor (VEGF) family includes key mediators of vasculogenesis and angiogenesis. VEGFs are secreted by various cells of epithelial and mesenchymal origin and by some immune cells in response to physiological and pathological stimuli. In addition, immune cells express VEGF receptors and/or co-receptors and can respond to VEGFs in an autocrine or paracrine manner. This immunological role of VEGFs has opened the possibility of using the VEGF inhibitors already developed to inhibit tumor angiogenesis also in combination approaches with different immunotherapies to enhance the action of effector T lymphocytes against tumor cells. This review pursues to examine the current understanding of the interplay between VEGFs and the immune system, while identifying key areas that require further evaluation.

Keywords: angiogenesis; immune cells; immunotherapy; tyrosine kinase inhibitor; vascular angiogenic growth factor.

Figure 1

Schematic representation of the different interactions among VEGFs and immune cells. VEGF-A has been reported to interact with monocytes/macrophages, dendritic cells, mesenchymal-derived suppressor cells (MDSCs), and regulatory T cells (T-reg) by acting as a chemoattractant factor [17,19,22]. VEGF-A increases polarization of T cells towards the T helper (h) 1 phenotype [21] and inhibits differentiation of dendritic cells and B cells [20]. PlGF increases chemokine release by monocytes/macrophages and induces differentiation of Natural killer cells and Th-17 lymphocytes [23,24,25]. VEGF-C and, probably, also VEGF-D, act as chemoattractants for monocytes/macrophages and induce activation of CD8+ T cells [26]. Conversely, VEGF-C can modulate lymphatic-mediated presentation of tumor antigens and inactivate CD8+ T cells [27]. Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com).

Figure 3

NRP-1 roles in immune cells. NRP-1 is expressed in different cells of the immune system. When expressed in T follicular helper (Tfh) cells, NRP-1 mediates B cell differentiation [81], whereas in plasmacytoid DCs, it induces the secretion of IFNα [82]. Human T cell lymphotropic virus type 1 (HTLV-1) enters myeloid DCs through NRP-1 and VEGF-A can block this infection [84]. Myeloid DCs can transfer NRP-1 and VEGF-A to T cells by trogocytosis [83]. DCs directly activate T cells through NRP-1 but also block T cell activation by secretion of SEMA3 [78]. Regulatory T cells (Tregs) are also directly activated by DCs but also indirectly by secretion of TGF-β that also blocks T cell activation [80]. SEMA-3A/NRP-1 interaction leads to increased migration of monocytes [73]. Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com).

Figure 2

Immune cell-mediated mechanisms of regulation of VEGF-A expression. Neutrophils and monocytes/macrophages release inflammatory cytokines (TNFα and IL-1β), which stimulate the secretion of VEGF-A by both endothelial and non-endothelial cells [40]. IL-9 induces VEGF-A release by human mast cells [41], whereas IL-4 inhibits the release of VEGF-A by human macrophages [42]. CD40-CD40L-mediated cell–cell contact can induce VEGF-A secretion by different cell types [43,44]. VEGF-A secretion by dendritic cells is induced by molecules such as TNFα, calcitriol, lipopolysaccharide (LPS), or prostaglandin (PG)E₂. Neutrophils augment VEGF-A availability by secretion of matrix metalloproteinases (MMPs) and heparinases [38], and hypoxia can induce T cells to secrete VEGF-A through hypoxia-inducible factor (HIF)-1 [21,45]. Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com).