Abstract 4746: Type I NKT cells mediate anti-tumor immunity through a TNF-α- and NOS-dependent pathway when stimulated with β-ManCer

Abstract

Abstract CD1d-restricted type I NKT cells have been shown to play a critical role in the induction of tumor immunity by producing IFN-γ, which activates effector arms such as NK cells and CD8+ T cells. It has been considered that IFN-γ is necessary for type I NKT cell-induced tumor immunity. In this study, we show that type I NKT cells can induce strong tumor immunity through an IFN-γ-independent pathway when activated with a new type of agonistic antigen, β-mannosylceramide (β-ManCer). The protection induced by β-ManCer treatment was completely abrogated in type I NKT cell deficient Jα18 KO mice. With the observations that in vitro activation of type I NKT cells by β-ManCer was blocked by anti-CD1d blocking monoclonal antibody and that β-ManCer-loaded CD1d dimers bind to type I NKT cells and stimulate type I NKT cell hybridomas in an APC-free system, we concluded that recognition of CD1d presented β-ManCer by a TCR of type I NKT cells is necessary for the protection. Surprisingly β-ManCer-induced protection was not abrogated in IFN-γ deficient mice, which is in contrast with the protection induced by a prototypic agonist α-galactosylceramide (α-GalCer). Instead, β-ManCer-induced protection was dependent on nitric oxide synthase (NOS) and TNF-α since blockade of either completely abrogated the protection while the blockade did not affect protection induced by α-GalCer. The conclusion that NKT cells activated with β-ManCer utilize a different pathway from that used by the cells activated with α-GalCer to enhance tumor immunity was confirmed with the observation that the combination of both antigens synergistically enhanced tumor immunity when suboptimal doses of each were used. These data demonstrate that NKT cells mediate tumor immunity through a TNF-α- and NOS-dependent pathway when stimulated with β-ManCer and that β-ManCer represents a new class of type I NKT cell agonist. Since we observed that human type I NKT cells also can be activated by β-ManCer, β-ManCer may provide a new intervention against cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4746. doi:10.1158/1538-7445.AM2011-4746