Abstract 5613: Beta-mannosylceramide: a novel NKT cell agonist which synergizes with alpha-galactocylceramide to induce protection against tumors

Abstract

Abstract Type I natural killer T (NKT) cells are a unique subset of T cells which express phenotypic and functional characteristics of both NK cells and T cells. NKT cells recognize glycolipid antigens presented by the non-classical MHC-like molecule CD1d. Upon stimulation with the prototypical type I NKT cell antigen α-galactosylceramide (α-GalCer), type I NKT cells promote tumor immunity through IFN-γ-dependent mechanims. In this study the ability of glycosylceramides with alterations of the sugar moiety to induce anti-tumor immune responses in an in vivo model of CT26 colon carcinoma metastasis to lungs of BALB/c mice was investigated. β-mannosylceramide (β-ManCer) induced strong tumor protection, while α-mannosylceramide and α-fucosylceramide did not. This is the first evidence of a glycosylceramide with a β-linked sugar moiety capable of inducing significant NKT cell-dependent anti-tumor immunity. We also confirmed that β-ManCer could protect at least as well as α-GalCer in a model of B16F10 melanoma lung metastasis in C57BL/6 mice. Interestingly, β-ManCer induced little cytokine production and retained protective activity in IFN-γ KO mice, unlike α-GalCer analogs which where completely dependent upon IFN-γ. The protection did not require CD8+ T cells, and was largely independent of NK cells. Blockade of nitric oxide synthase or TNF-α significantly reversed the β-ManCer-induced protection but had no effect on tumor protection for the α-GalCer analogs. Thus, contrary to α-GalCer, β-ManCer protects through a novel TNF-α and NOS-dependent, IFN-γ-independent mechanism. Consistent with the conclusion that β-ManCer and α-GalCer induce tumor immunity by distinct mechanisms, simultaneous administration of sub-therapeutic doses of these glycolipids resulted in synergistic reduction in the number of lung metastases. The distinct mechanism of action and ability to synergize with α-GalCer may suggest that β-ManCer represents a new class of NKT agonists with novel clinical applications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5613.