Combined stimulation with interleukin-18 and CpG induces murine natural killer dendritic cells to produce IFN-gamma and inhibit tumor growth.
Natural killer dendritic cells (NKDC) are a novel subtype of dendritic cells with natural killer (NK) cell properties. IFN-gamma is a pleiotropic cytokine that plays an important role in the innate immune response to tumors. Based on our previous finding that the combination of Toll-like receptor 9 ligand CpG and interleukin (IL)-4 stimulates NKDC to produce IFN-gamma, we hypothesized that NKDC are the major IFN-gamma-producing dendritic cell subtype and may play a significant role in the host antitumor response. We found that under several conditions in vitro and in vivo NKDC accounted for the majority of IFN-gamma production by murine spleen CD11c(+) cells. IL-18 alone induced NKDC to secrete IFN-gamma, and the combination of IL-18 and CpG resulted in a synergistic increase in IFN-gamma production, both in vitro and in vivo. NK cells made 26-fold less IFN-gamma under the same conditions in vitro, whereas dendritic cells produced a negligible amount. The mechanism of IFN-gamma secretion by NKDC depended on IL-12. NKDC selectively proliferated in vitro and in vivo in response to the combination of IL-18 and CpG. Systemic treatment with IL-18 and CpG reduced the number of B16F10 melanoma lung metastases. The mechanism depended on NK1.1(+) cells, as their depletion abrogated the effect. IL-18 and CpG activated NKDC provided greater tumor protection than NK cells in IFN-gamma(-/-) mice. Thus, NKDC are the major dendritic cell subtype to produce IFN-gamma. The combined use of IL-18 and CpG is a viable strategy to potentiate the antitumor function of NKDC.
Chaudhry
Umer I
UI
Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Kingham
T Peter
TP
Plitas
George
G
Katz
Steven C
SC
Raab
Jesse R
JR
DeMatteo
Ronald P
RP
D000818:Animals; D004247:DNA / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004357:Drug Synergism; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides
C423449:CpG ODN 1826; D020382:Interleukin-18; D009838:Oligodeoxyribonucleotides; D018664:Interleukin-12; D007371:Interferon-gamma; D004247:DNA