NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model

Autor: Jody L. Lutterman, Sean M. Mcgurran, Laxma G. Reddy, Kevin S. Gorski, Calin D. Dumitru, Elaine A. Egging, Kenneth E. Lipson, Melissa M. Piri, Gary W. Gullikson, Dave D. Johnson, Felicia R. Cochran, Mark A. Tomai, Mary A. Antonysamy, Joel Proksch
Rok vydání: 2008
Předmět:
Zdroj: Cancer Immunology, Immunotherapy. 58:575-587
ISSN: 1432-0851
0340-7004
DOI: 10.1007/s00262-008-0581-7
Popis: 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.
Databáze: OpenAIRE
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