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 4

In vitro and in vivo cytokine production induced by glycolipid treatment.

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In vitro and in vivo cytokine production induced by glycolipid treatment...
(A) CT26 cells (5 × 105 cells) were injected i.v. into the tail veins of BALB/c mice. Mice (5 mice per group) were treated with 50 pmoles (black symbols) or 5 pmoles (white symbols) α-GalCer (triangles), β-ManCer (squares), C20:2 (circles), AH04-2 (diamonds), or OCH (inverted triangles) within 1 hour after tumor challenge. Mice were sacrificed 14–16 days after tumor challenge, and lung metastases were enumerated. *P < 0.05 compared with vehicle control. Vertical bars indicate the interquartile range, and horizontal bars indicate the median value. Each symbol represents an individual mouse. (B) BALB/c splenocytes were stimulated with various concentrations of glycolipid or vehicle control for 48 hours, and the concentrations of IFN-γ, IL-4, IL-13, and TNF-α in supernatant were determined by ELISA. Each data point represents mean ± SD of triplicates. (C) BALB/c mice (5 mice per group) were challenged with CT26 (5 × 105) i.v., followed by 50 pmoles glycolipid or vehicle control i.p. at time 0. Mice were bled retro-orbitally at 0, 3, 6, 12, and 24 hours, and the amount of IFN-γ, IL-4, IL-13, IL-12(p70), and TNF-α in plasma was determined by Bio-plex. Each data point represents mean ± SD of triplicates. Representative experiments of at least 2 repeats are shown. Due to substantial overlap of data points corresponding to little or no detectable cytokine, some data points are not visible, but all compounds shown in legend were tested.