Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity
Jessica J. O’Konek, … , Jay A. Berzofsky, Masaki Terabe
Jessica J. O’Konek, … , Jay A. Berzofsky, Masaki Terabe
Published January 18, 2011
Citation Information: J Clin Invest. 2011;121(2):683-694. https://doi.org/10.1172/JCI42314.
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Research Article Immunology

Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity

Abstract

Type 1 or invariant NKT (iNKT) cell agonists, epitomized by α-galactosylceramide, protect against cancer largely by IFN-γ–dependent mechanisms. Here we describe what we believe to be a novel IFN-γ–independent mechanism induced by β-mannosylceramide, which also defines a potentially new class of iNKT cell agonist, with an unusual β-linked sugar. Like α-galactosylceramide, β-mannosylceramide directly activates iNKT cells from both mice and humans. In contrast to α-galactosylceramide, protection by β-mannosylceramide was completely dependent on NOS and TNF-α, neither of which was required to achieve protection with α-galactosylceramide. Moreover, at doses too low for either alone to protect, β-mannosylceramide synergized with α-galactosylceramide to protect mice against tumors. These results suggest that treatment with β-mannosylceramide provides a distinct mechanism of tumor protection that may allow efficacy where other agonists have failed. Furthermore, the ability of β-mannosylceramide to synergize with α-galactosylceramide suggests treatment with this class of iNKT agonist may provide protection against tumors in humans.

Authors

Jessica J. O’Konek, Petr Illarionov, Deborah Stewart Khursigara, Elena Ambrosino, Liat Izhak, Bernard F. Castillo II, Ravinder Raju, Maryam Khalili, Hee-Yong Kim, Amy R. Howell, Gurdyal S. Besra, Steven A. Porcelli, Jay A. Berzofsky, Masaki Terabe

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Figure 7

β-ManCer also protects against B16F10 melanoma metastases in C57BL/6 mice.

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β-ManCer also protects against B16F10 melanoma metastases in C57BL/6 mic...
B16F10 cells (5 × 105 cells) were injected i.v. into the tail veins of C57BL/6 mice (5 mice per group). (A) The indicated doses of glycolipid were administered within 1 hour after tumor challenge. (B) Mice were treated with l-NAME (white symbols) or the inactive stereoisomer d-NAME (black symbols) twice on days 0 and 1 and once daily for days 2–12. After NAME injections, 500 pmoles α-GalCer or 50 pmoles β-ManCer was administered. (C) WT mice were treated with etanercept (TNF-αR-Fc) (white symbols) or human IgG (black symbols) every other day, beginning immediately after tumor challenge. After antibody injections, 500 pmoles α-GalCer or 50 pmoles β-ManCer was administered. Mice were sacrificed 12 days after tumor challenge, and lung metastases were enumerated. *P < 0.05 compared with respective vehicle control. Representative experiments of 2 repeats are shown. Vertical bars indicate the interquartile range, and horizontal bars indicate the median value. Each symbol represents an individual mouse.