title: NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model.
abstract: Innate immune stimulation with Toll-like receptor (TLR) agonists is a proposed modality for immunotherapy of melanoma. Here, a TLR7/8 agonist, 3M-011, was used effectively as a single systemic agent against disseminated mouse B16-F10 melanoma. The investigation of the mechanism of antitumor action revealed that the agonist had no direct cytotoxic effects on tumor cells tested in vitro. In addition, 3M-011 retained its effectiveness in scid/B6 mice and scid/NOD mice, eliminating the requirement for T and B cells, but lost its activity in beige (bg/bg) and NK1.1-immunodepleted mice, suggesting a critical role for natural killer (NK) cells in the antitumor response. NK cytotoxicity was enhanced in vivo by the TLR7/8 agonist; this activation was long lasting, as determined by sustained expression of the activation marker CD69. Also, in human in vitro studies, 3M-011 potentiated NK cytotoxicity. TLR7/8-mediated NK-dependent antitumor activity was retained in IFN-alpha/beta receptor-deficient as well as perforin-deficient mice, while depletion of IFN-gamma significantly decreased the ability of 3M-011 to delay tumor growth. Thus, IFN-gamma-dependent functions of NK cell populations appear essential for cancer immunotherapy with TLR7/8 agonists.
authors.affiliation: Department of Pharmacology, 3M Pharmaceuticals, St Paul, MN 55144, USA. calin_dumitru@merck.com
authors.forename: Calin D
authors.initials: CD
authors.lastname: Dumitru
authors.forename: Mary A
authors.initials: MA
authors.lastname: Antonysamy
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Gorski
authors.forename: Dave D
authors.initials: DD
authors.lastname: Johnson
authors.forename: Laxma G
authors.initials: LG
authors.lastname: Reddy
authors.forename: Jody L
authors.initials: JL
authors.lastname: Lutterman
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Piri
authors.forename: Joel
authors.initials: J
authors.lastname: Proksch
authors.forename: Sean M
authors.initials: SM
authors.lastname: McGurran
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Egging
authors.forename: Felicia R
authors.initials: FR
authors.lastname: Cochran
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tomai
authors.forename: Gary W
authors.initials: GW
authors.lastname: Gullikson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D011804:Quinolines / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
chemical_list: C526116:3M 001; D000970:Antineoplastic Agents; D007093:Imidazoles; D016328:NF-kappa B; D011804:Quinolines; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D007371:Interferon-gamma
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