Cancer Immunology, Immunotherapy

, Volume 56, Issue 6, pp 761–770

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

  • Kousaku Mimura
  • Koji Kono
  • Akihiro Takahashi
  • Yoshihiko Kawaguchi
  • Hideki Fujii
Original Article

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.

Keywords

VEGF DC KDR OK-432 LPS 

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Kousaku Mimura
    • 1
  • Koji Kono
    • 1
  • Akihiro Takahashi
    • 1
  • Yoshihiko Kawaguchi
    • 1
  • Hideki Fujii
    • 1
  1. 1.First Department of SurgeryUniversity of YamanashiChuo-cityJapan

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