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 2

β-ManCer, but not α-ManCer or α-FucCer, induced strong protection against CT26 lung metastasis in an iNKT cell–dependent manner.

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β-ManCer, but not α-ManCer or α-FucCer, induced strong protection agains...
CT26 cells (5 × 105 cells) were injected i.v. into the tail vein of BALB/c mice (5 mice per group), and glycolipids were administered within 1 hour after tumor challenge. Mice were sacrificed 14–16 days after tumor challenge, and lung metastases were enumerated. (A) Mice were treated with vehicle (black diamonds), α-FucCer (white circles), α-ManCer (white squares), 50 pmoles β-ManCer (black squares), or 50 pmoles α-GalCer (black triangles). (B) Mice were treated with vehicle (black diamonds), β-GalCer (white triangles), or 50 pmoles β-ManCer (black squares). (C) WT BALB/c (black symbols) or Jα18–/– (white symbols) mice (5 mice per group) were treated with vehicle (circles) or 50 pmoles β-ManCer (squares). *P < 0.05 compared with vehicle control. Representative experiments of at least 2 repeats are shown. Vertical bars indicate the interquartile range, and horizontal bars indicate the median value. Each symbol represents an individual mouse.