Erschienen in:
01.04.2009 | Original Article
NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model
verfasst von:
Calin D. Dumitru, Mary A. Antonysamy, Kevin S. Gorski, Dave D. Johnson, Laxma G. Reddy, Jody L. Lutterman, Melissa M. Piri, Joel Proksch, Sean M. McGurran, Elaine A. Egging, Felicia R. Cochran, Kenneth E. Lipson, Mark A. Tomai, Gary W. Gullikson
Erschienen in:
Cancer Immunology, Immunotherapy
|
Ausgabe 4/2009
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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-α/β receptor-deficient as well as perforin-deficient mice, while depletion of IFN-γ significantly decreased the ability of 3M-011 to delay tumor growth. Thus, IFN-γ-dependent functions of NK cell populations appear essential for cancer immunotherapy with TLR7/8 agonists.