IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide.
Alpha-galactosylceramide (alpha-GalCer), which is a specific ligand for CD1d-restricted variable-alpha14 chain (V(alpha)14) natural killer T (NKT) cells, exerts a potent antitumor effect. We recently demonstrated that interferon-gamma (IFN-gamma) secreted by both NKT cells and NK cells plays a critical role in mediating the antimetastatic effect of alpha-GalCer; however, the IFN-gamma-dependent antitumor mechanisms remain poorly defined. In the present study, we demonstrate IFN-gamma-dependent inhibition of tumor angiogenesis by alpha-GalCer. In alpha-GalCer-treated mice, subcutaneous tumor growth and tumor-induced angiogenesis were inhibited in an IFN-gamma-dependent manner. The alpha-GalCer-activated splenic or hepatic mononuclear cells inhibited murine endothelial cell proliferation in vitro, and this inhibitory effect was mediated mostly by IFN-gamma produced by NKT cells and NK cells. NK cell depletion resulted in significant but partial inhibition of tumor growth and angiogenesis in vivo. These results suggest that the IFN-gamma-mediated inhibition of tumor angiogenesis is critically involved in the effector mechanisms of antitumor effects evoked by alpha-GalCer.
Hayakawa
Yoshihiro
Y
Department of Pathogenic Biochemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Japan. y.hayakawa@pmci.unimelb.edu.au
Takeda
Kazuyoshi
K
Yagita
Hideo
H
Smyth
Mark J
MJ
Van Kaer
Luc
L
Okumura
Ko
K
Saiki
Ikuo
I
D000818:Animals; D005699:Galactosylceramides / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000276:immunology
D005699:Galactosylceramides; D008024:Ligands; D007371:Interferon-gamma