Small-molecule inhibitors of vascular adhesion protein-1 reduce the accumulation of myeloid cells into tumors and attenuate tumor growth in mice.
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.
MediCity Research Laboratory, University of Turku, Turku, Finland.
Fumiko
F
Marttila-Ichihara
Karolien
K
Castermans
Kaisa
K
Auvinen
Mirjam G A
MG
Oude Egbrink
Sirpa
S
Jalkanen
Arjan W
AW
Griffioen
Marko
M
Salmi
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000499:Allylamine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006131:Growth Inhibitors / Q000627:therapeutic use*; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D012663:Semicarbazides / Q000627:therapeutic use
C526615:3-fluoro-2-(4-methoxybenzyl)allylamine; D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D012663:Semicarbazides; C010059:carbamylhydrazine; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse