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

Abstract
It has been suggested that immunosuppressive cytokines such as transforming growth factor beta (TGF-beta) 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 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.
AuthorsJunji Wada, Hiroyuki Suzuki, Ryouta Fuchino, Akio Yamasaki, Shuntaro Nagai, Kousuke Yanai, Kenichiro Koga, Masafumi Nakamura, Masao Tanaka, Takashi Morisaki, Mitsuo Katano
JournalAnticancer research (Anticancer Res) Vol. 29 Issue 3 Pg. 881-8 (Mar 2009) ISSN: 0250-7005 [Print] Greece
PMID19414323 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Vascular Endothelial Growth Factor Receptor-2
Topics
  • Adult
  • Aged
  • Angiogenesis Inhibitors (therapeutic use)
  • Antibodies, Monoclonal (therapeutic use)
  • Antibodies, Monoclonal, Humanized
  • Bevacizumab
  • Dendritic Cells (transplantation)
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunotherapy
  • Male
  • Middle Aged
  • Neoplasms (immunology, therapy)
  • Pleural Effusion, Malignant (immunology, therapy)
  • T-Lymphocytes, Regulatory (immunology)
  • Vaccination
  • Vascular Endothelial Growth Factor A (antagonists & inhibitors, physiology)
  • Vascular Endothelial Growth Factor Receptor-2 (metabolism)

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