title: IL-15 and type I interferon are required for activation of tumoricidal NK cells by virus-infected dendritic cells.
abstract: There is increasing evidence that natural killer (NK) cells play an important role in antitumor immunity following dendritic cell (DC) vaccination. Little is known, however, about the optimal stimulation of DCs that favors NK activation in tumor-bearing hosts. In this study, we demonstrate that treatment with toll-like receptor (TLR) ligands and infection with a mutant vesicular stomatitis virus (VSV-ΔM51) both induced DC maturation. Further, inoculation of these DCs led to robust NK-mediated protection against tumor challenge. Strikingly, only VSV-ΔM51-infected DCs were capable of suppressing the growth of established tumors, suggesting that additional signals provided by viral infection may be required to activate tumoricidal NK cells in tumor-bearing hosts. VSV-ΔM51 infection of DCs induced greater type I interferon (IFN I) production than TLR ligand treatment, and disruption of the IFN I pathway in DCs eliminated their ability to induce NK activation and tumor protection. However, further studies indicated that IFN I alone was not sufficient to activate NK cells, especially in the presence of a tumor, and DC-derived IL-15 was additionally required for tumoricidal NK activation. These results suggest that induction of IFN I by VSV-ΔM51 allows DCs to overcome tumor-associated immunosuppression and facilitate IL-15-mediated priming of tumoricidal NK cells. Thus, the mode of DC maturation should be carefully considered when designing DC-based cancer immunotherapies.
authors.affiliation: Department of Pathology and Molecular Medicine and Medical Sciences Program, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Boudreau
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Stephenson
authors.forename: Fuan
authors.initials: F
authors.lastname: Wang
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
authors.forename: Laurel L
authors.initials: LL
authors.lastname: Lenz
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rosenthal
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Bramson
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D018116:Vesiculovirus / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D019409:Interleukin-15; D008024:Ligands; D051193:Toll-Like Receptors