Small-molecule inhibitors of vascular adhesion protein-1 reduce the accumulation of myeloid cells into tumors and attenuate tumor growth in mice

J Immunol. 2010 Mar 15;184(6):3164-73. doi: 10.4049/jimmunol.0901794. Epub 2010 Feb 12.


Vascular adhesion protein-1 (VAP-1) is an endothelial, cell surface-expressed oxidase involved in leukocyte traffic. The adhesive function of VAP-1 can be blocked by anti-VAP-1 Abs and small-molecule inhibitors. However, the effects of VAP-1 blockade on antitumor immunity and tumor progression are unknown. In this paper, we used anti-VAP-1 mAbs and small-molecule inhibitors of VAP-1 in B16 melanoma and EL-4 lymphoma tumor models in C57BL/6 mice. Leukocyte accumulation into tumors and neoangiogenesis were evaluated by immunohistochemistry, flow cytometry, and intravital videomicroscopy. We found that both anti-VAP-1 Abs and VAP-1 inhibitors reduced the number of leukocytes in the tumors, but they targeted partially different leukocyte subpopulations. Anti-VAP-1 Abs selectively inhibited infiltration of CD8-positive lymphocytes into tumors and had no effect on accumulation of myeloid cells into tumors. In contrast, the VAP-1 inhibitors significantly reduced only the number of proangiogenic Gr-1(+)CD11b(+) myeloid cells in melanomas and lymphomas. Blocking of VAP-1 by either means left tumor homing of regulatory T cells and type 2 immune-suppressing monocytes/macrophages intact. Notably, VAP-1 inhibitors, but not anti-VAP-1 Abs, retarded the growth of melanomas and lymphomas and reduced tumor neoangiogenesis. The VAP-1 inhibitors also reduced the binding of Gr-1(+) myeloid cells to the tumor vasculature. We conclude that tumors use the catalytic activity of VAP-1 to recruit myeloid cells into tumors and to support tumor progression. Small-molecule VAP-1 inhibitors therefore might be a potential new tool for immunotherapy of tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / therapeutic use
  • Allylamine / analogs & derivatives
  • Allylamine / therapeutic use
  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
  • Amine Oxidase (Copper-Containing) / biosynthesis
  • Amine Oxidase (Copper-Containing) / immunology*
  • Animals
  • Antibodies, Blocking / therapeutic use
  • Antibodies, Monoclonal / therapeutic use
  • Cell Adhesion Molecules / antagonists & inhibitors*
  • Cell Adhesion Molecules / biosynthesis
  • Cell Adhesion Molecules / immunology*
  • Cell Line, Tumor
  • Cell Migration Inhibition / drug effects
  • Cell Migration Inhibition / immunology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Growth Inhibitors / therapeutic use*
  • Lymphoma, T-Cell / immunology*
  • Lymphoma, T-Cell / pathology
  • Lymphoma, T-Cell / therapy
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology*
  • Myeloid Cells / pathology*
  • Semicarbazides / therapeutic use


  • 3-fluoro-2-(4-methoxybenzyl)allylamine
  • Adjuvants, Immunologic
  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Cell Adhesion Molecules
  • Enzyme Inhibitors
  • Growth Inhibitors
  • Semicarbazides
  • carbamylhydrazine
  • Allylamine
  • Amine Oxidase (Copper-Containing)
  • semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse