The contribution of vascular endothelial growth factor to the induction of regulatory T- cells in malignant effusions

It has been suggested that immunosuppressive cytokines such as transforming growth factor β(TGF-β)and interleukin 10 play an important role in the induction and/or maintenance of regulatory T-cells(Tregs)in patients with cancer. In the present study, whether or not vascular endothelial growth factor(VEGF)contributes to the induction and/or maintenance of Tregs was examined, because of experience with a patient in whom a positive correlation between VEGF concentration and the percentage of Tregs(% Tregs)among the total CD4⁺ T-cells in the pleural effusion was found during dendritic cell activated lymphocyte therapy. CD4⁺CD25^high T-cells were estimated as Tregs in the present study. In an in vitro experimental system, VEGF-containing malignant effusions increased the % Tregs in autologous peripheral blood mononuclear cells(PBMCs), which could be suppressed by the addition of a humanized monoclonal anti-VEGF antibody(bevacizumab[Avastin]). When VEGF-producing hepatic carcinoma cells were mix-cultured with PBMCs, the % Tregs increased and this increase was also suppressed by the addition of bevacizumab. Whether or not bevacizumab can affect the % Tregs of PBMCs in patients with colon cancer was also examined.Three out of four patients showed a significant decrease of the % Tregs after the intravenous injection of bevacizumab Interestingly, the expression of VEGF receptor 2(VEGFR-2)was higher in Tregs than in other CD4⁺ T-cells.Taken together, the data presented here indicate a contribution of VEGF to induction and/or maintenance of Tregs in patients with cancer.