title: VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2.
abstract: The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis is well characterized; nevertheless, it is also a key element in promoting tumor evasion of the immune system by downregulating dendritic cell maturation and thus T cell activation. We sought to investigate the possible direct effect of VEGF on T cell activation and through which type of VEGF receptor (VEGFR) it exerts this effect. Circulating T cells from healthy donors and ovarian cancer patients were expanded in cultures with anti-CD3 and IL-2 with or without VEGF for 14 days, and the number of T cells was assessed. Cultured T cells were also tested for their cytotoxic activity in a standard 4-hr (51) Cr-release assay, and the expression of VEGFRs 1, 2 and 3 was assayed by flow cytometry, immunocytochemistry and Western blotting. To assess the ability of activated T cells to secrete VEGF, levels in culture supernatants were measured by enzyme linked immunosorbent assay. The addition of VEGF in cultures significantly reduced T cell proliferation in a dose-dependent manner. Protein expression studies demonstrated that CD3(+)  T cells express VEGFR-2 on their surface upon activation. Experiments with anti-VEGFR-2 antibodies showed that the direct suppressive effect of VEGF on T cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells and that activated T cells secrete VEGF in the culture environment. Overall, our study shows that T cells secret VEGF and expresses VEGFR-2 upon activation. VEGF directly suppresses T cell activation via VEGF receptor type 2.
authors: Department of Clinical Therapeutics, Medical School, University of Athens, Athens, Greece.
authors: Apostolos C
authors: AC
authors: Ziogas
authors: Nikos G
authors: NG
authors: Gavalas
authors: Marinos
authors: M
authors: Tsiatas
authors: Ourania
authors: O
authors: Tsitsilonis
authors: Ekaterini
authors: E
authors: Politi
authors: Evangelos
authors: E
authors: Terpos
authors: Alexandros
authors: A
authors: Rodolakis
authors: George
authors: G
authors: Vlahos
authors: Nikolaos
authors: N
authors: Thomakos
authors: Dimitrios
authors: D
authors: Haidopoulos
authors: Aristidis
authors: A
authors: Antsaklis
authors: Meletios A
authors: MA
authors: Dimopoulos
authors: Aristotle
authors: A
authors: Bamias
mesh_terms: D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D010051:Ovarian Neoplasms / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2