Beta-mannosylceramide represents a new class of NKT agonists that induces tumor immunity by a novel IFN-γ-independent mechanism. (89.7)

Abstract

Abstract Type I NKT cells are a unique lymphocyte population which recognize lipid antigens presented by the non-classical MHC-like molecule CD1d. Activation of type I NKT cells by α-galactosylceramide (α-GC) induces tumor immunity by IFN-γ dependent mechanisms. In this study, we characterized how modifications of the sugar head group of α-GC impacted tumor protection in an in vivo mouse model of lung metastasis. β-mannosylceramide (β-ManCer), but not α-mannosylceramide or α-fucosylceramide, induced strong type I NKT cell-dependent tumor immunity. Because this is the first report of a β-linked glycosylcermide capable of inducing significant type I NKT cell-mediated tumor protection, we further characterized the mechanism by which β-ManCer induced tumor elimination. Interestingly, unlike α-GC and its analogs which protected through IFN-γ dependent mechanisms, β-ManCer induced very little cytokine production both in vitro and in vivo and retained protection in the absence of IFN-γ. Rather, β-ManCer protected through a TNF-α and nitric oxide synthase-dependent mechanism novel for NKT cells. Simultaneous administration of sub-therapeutic doses of β-ManCer and α-GC resulted in synergistic reduction in tumor burden, supporting the conclusion that these glycolipids work through different mechanisms. The distinct mechanism of action of β-ManCer and its ability to synergize with α-GC suggest that β-ManCer is the first representative of a new class of type I NKT cell agonists.