IFN-γ-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, α-galactosylceramide

Alpha-galactosylceramide (α-GalCer), which is a specific ligand for CD1d-restricted variable-α14 chain (Vα14) natural killer T (NKT) cells, exerts a potent antitumor effect. We recently demonstrated that interferon-γ (IFN-γ) secreted by both NKT cells and NK cells plays a critical role in mediating the anti-metastatic effect of α-GalCer; however, the IFN-γ-dependent antitumor mechanisms remain poorly defined. In the present study, we demonstrate IFN-γ-dependent inhibition of tumor angiogenesis by α-Gal-Cer. In α-GalCer-treated mice, subcutaneous tumor growth and tumor-induced angiogenesis were inhibited in an IFN-γdependent manner. The α-GalCer-activated splenic or hepatic mononuclear cells inhibited murine endothelial cell proliferation in vitro, and this inhibitory effect was mediated mostly by IFN-γ 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 IFNγ-mediated inhibition of tumor angiogenesis is critically involved in the effector mechanisms of antitumor effects evoked by α-GalCer.