Abstract 1556: α-mannosylceramide, a new NKT cell agonist, induces tumor immunity without anergy induction in NKT cells

Abstract

Abstract NKT cells are CD1d-restricted T cells recognizing lipid antigens. When NKT cells are activated with a prototypic antigen, α-galactosylceramide (α-GalCer), they induce strong tumor immunity. Strong preclinical evidence for α-GalCer's ability to induce tumor immunity through NKT cell-activation led to translation into therapy of cancer patients. However, so far minimal success has been achieved in patients. We reasoned that having an α-linked sugar moiety in the structure of α-GalCer can be a target for anti-α-linked galactose natural antibodies, which are a cause of acute xenograft rejection, and which might abrogate the biological activity of α-GalCer. After testing multiple glycosylceramides with potential agonistic activity for NKT cells, we discovered that α-mannosylceramide (α-ManCer) has strong activity to induce tumor immunity through a TNF-α- and NOS-dependent mechanism that is distinct from the IFN-γ dependent protection induced by α-GalCer. Another downside of α-GalCer treatment is induction of long-lasting anergy in activated NKT cells. Since we did not observe massive cytokine production with α-ManCer, in contrast to α-GalCer, we asked whether this new compound activates NKT cells without inducing long-lasting anergy in vivo. In contrast to α-GalCer, α-ManCer did not induce long-lasting anergy of activated NKT cells. This was correlated with the observation that α-ManCer induced only a short term expression of PD-1 on activated NKT cells, which has been reported to be responsible for α-GalCer-induced long-term anergy. Furthermore, while prior treatment with α-GalCer abrogated the protective effect of either α-GalCer or α-ManCer against CT26 colon carcinoma tumor challenge for at least two months, the pre-treatment with α-ManCer had no effect on the protection induced by either NKT cell agonist. Since α-ManCer can activate human NKT cells, this new NKT cell agonist may provide a better opportunity for NKT cell targeted immunotherapy in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1556. doi:1538-7445.AM2012-1556