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

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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.

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Acknowledgment

This work was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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Authors and Affiliations

  1. First Department of Surgery, University of Yamanashi, 1110 shimokato, Chuo-city, Yamanashi, 409-3898, Japan

    Kousaku Mimura, Koji Kono, Akihiro Takahashi, Yoshihiko Kawaguchi & Hideki Fujii

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  1. Kousaku Mimura
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  2. Koji Kono
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  3. Akihiro Takahashi
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  4. Yoshihiko Kawaguchi
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  5. Hideki Fujii
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Correspondence to Koji Kono.

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This work was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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Mimura, K., Kono, K., Takahashi, A. et al. Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2. Cancer Immunol Immunother 56, 761–770 (2007). https://doi.org/10.1007/s00262-006-0234-7

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  • DOI: https://doi.org/10.1007/s00262-006-0234-7

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