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 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.
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Junji
J
Wada
Hiroyuki
H
Suzuki
Ryouta
R
Fuchino
Akio
A
Yamasaki
Shuntaro
S
Nagai
Kousuke
K
Yanai
Kenichiro
K
Koga
Masafumi
M
Nakamura
Masao
M
Tanaka
Takashi
T
Morisaki
Mitsuo
M
Katano
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003713:Dendritic Cells / Q000637:transplantation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D016066:Pleural Effusion, Malignant / Q000276:immunology* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014611:Vaccination; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2