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

Jessica J. O'Konek, Petr Illarionov, Deborah Stewart Khursigara, Elena Ambrosino, Liat Izhak, Bernard F. Castillo, 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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35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)683-694
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number2
DOIs
StatePublished - Feb 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    O'Konek, J. J., Illarionov, P., Khursigara, D. S., Ambrosino, E., Izhak, L., Castillo, B. F., Raju, R., Khalili, M., Kim, H. Y., Howell, A. R., Besra, G. S., Porcelli, S. A., Berzofsky, J. A., & Terabe, M. (2011). Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity. Journal of Clinical Investigation, 121(2), 683-694. https://doi.org/10.1172/JCI42314