Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity.
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.
Jessica J
JJ
O'Konek
Petr
P
Illarionov
Deborah Stewart
DS
Khursigara
Elena
E
Ambrosino
Liat
L
Izhak
Bernard F
BF
Castillo
Ravinder
R
Raju
Maryam
M
Khalili
Hee-Yong
HY
Kim
Amy R
AR
Howell
Gurdyal S
GS
Besra
Steven A
SA
Porcelli
Jay A
JA
Berzofsky
Masaki
M
Terabe
D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000737:chemistry* / Q000276:immunology*; D005260:Female; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology*
D002518:Ceramides; D005699:Galactosylceramides; C493154:alpha-galactosylceramide
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