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

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