Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2

Abstract

Dendritic cells (DCs) are the most potent antigen-presenting cells and play a central role in the host-antitumor immunity. Since it has been reported that vascular endothelial growth factor (VEGF) inhibits the functional maturation of immature-DCs and impairs DC differentiation, it is important to elucidate the mechanisms of VEGF-induced DC-dysfunction. To investigate the effects of VEGF against human mature DCs, we investigated how VEGF affects mature DCs with regards to phenotype, induction of apoptosis, IL-12(p70) production and the antigen-presenting function evaluated by allogeneic mixed leukocyte reaction (allo-MLR). We generated monocyte-derived DCs matured with lipopolysaccharide, OK-432 or pro-inflammatory cytokine cocktails. As a result, VEGF treatment did not alter the mature DCs with regard to phenotype, IL-12(p70) production and induction of apoptosis. As a novel and important finding, VEGF inhibited the ability of mature DCs to stimulate allogeneic T cells. Furthermore, this VEGF-induced DC dysfunction was mainly mediated by VEGF receptor-2 (VEGF R2). These observations were confirmed by the findings that the VEGF-induced DC dysfunction was recovered by anti-human VEGF neutralizing mAb or anti-human VEGF R2 blocking mAb, and that placenta growth factor (PlGF), VEGF R1-specific ligand, did not have any effect against mature DCs. Some modalities aiming at reversing mature-DC dysfunction induced by VEGF will be needed in order to induce the effective antitumor immunity.

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients

“…Dikov reported that VEGF acted on early stage of DC differentiation but not later phase of maturation. On the other hand, Mimura et al [34] recently reported, using matured human monocyte-derived DC, that VEGF did not affect DC phenotype, but inhibited allostimulatory capacity through VEGFR2 receptor. Thus, more studies are needed to reveal the detailed mechanism of VEGF effect on human DC.…”

“…This seemed to overestimate the percentage of blood DC (2.06 +/−1.57% of the mononuclear cells by this method) compared with the percentage generally reported in the literature (data not shown). To improve upon the method of DC quantification, we next used a different antibody cocktail consisting of antibodies against CD3, 14,15,16,19,20,34, and 56, and gated on the lineage negative, HLA-DR + cells (see Figure 1, region R2). Because this method was reproducible (coefficient of variance of 3.8% for three replicate analyses), it was used throughout the remainder of this report.…”

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…Another in vitro study used embryonic stem cells to show that the DC maturation mainly depends on VEGFR1 activation [59]. However, mature DCs function to abrogate T cells by VEGF may depend on VEGFR2 activation [60]. Recently, Marti et al showed that VEGF can not only regulate DC maturation but also induce immunosuppressive phenotype through the production of IDO [61].…”

ATP confers tumorigenic properties to dendritic cells by inducing amphiregulin secretion

“…3 VEGF-A was also reported to inhibit the function of mature DCs. 4 Immune cells such as tumor-associated macrophages and T cells were also reported to regulate angiogenesis through the secretion of potent angiogenic mediators such as angiopoietin-2 and interleukin-17 (IL-17). 5,6 We demonstrated previously that ATP up-regulates the expression by monocyte-derived DCs (MoDCs) of numerous genes that may play a role in immunosuppression, in particular thrombospondin-1 and indoleamine 2,3-dioxygenase.…”