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Reciprocal regulation of activating and inhibitory Fc{gamma} receptors by TLR7/8 activation: implications for tumor immunotherapy.

AbstractPURPOSE:
Activation of Toll-like receptors (TLR) 7 and 8 by engineered agonists has been shown to aid in combating viruses and tumors. Here, we wished to test the effect of TLR7/8 activation on monocyte Fcgamma receptor (FcgammaR) function, as they are critical mediators of antibody therapy.
EXPERIMENTAL DESIGN:
The effect of the TLR7/8 agonist R-848 on cytokine production and antibody-dependent cellular cytotoxicity by human peripheral blood monocytes was tested. Affymetrix microarrays were done to examine genomewide transcriptional responses of monocytes to R-848 and Western blots were done to measure protein levels of FcgammaR. Murine bone marrow-derived macrophages from WT and knockout mice were examined to determine the downstream pathway involved with regulating FcgammaR expression. The efficacy of R-848 as an adjuvant for antibody therapy was tested using a CT26-HER2/neu solid tumor model.
RESULTS:
Overnight incubation with R-848 increased FcgammaR-mediated cytokine production and antibody-dependent cellular cytotoxicity in human peripheral blood monocytes. Expression of FcgammaRI, FcgammaRIIa, and the common gamma-subunit was increased. Surprisingly, expression of the inhibitory FcgammaRIIb was almost completely abolished. In bone marrow-derived macrophage, this required TLR7 and MyD88, as R-848 did not increase expression of the gamma-subunit in TLR7(-/-) nor MyD88(-/-) cells. In a mouse solid tumor model, R-848 treatment superadditively enhanced the effects of antitumor antibody.
CONCLUSIONS:
These results show an as-yet-undiscovered regulatory and functional link between the TLR7/8 and FcgammaR pathways. This suggests that TLR7/8 agonists may be especially beneficial during antibody therapy.
AuthorsJonathan P Butchar, Payal Mehta, Steven E Justiniano, Kristan D Guenterberg, Sri-Vidya Kondadasula, Xiaokui Mo, Mahesh Chemudupati, Thirumala-Devi Kanneganti, Amal Amer, Natarajan Muthusamy, David Jarjoura, Clay B Marsh, William E Carson 3rd, John C Byrd, Susheela Tridandapani
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 7 Pg. 2065-75 (Apr 1 2010) ISSN: 1078-0432 [Print] United States
PMID20332325 (Publication Type: Evaluation Studies, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2010 AACR.
Chemical References
  • Antineoplastic Agents
  • Cytokines
  • Imidazoles
  • Immunologic Factors
  • Receptors, IgG
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • resiquimod
Topics
  • Animals
  • Antibody-Dependent Cell Cytotoxicity (drug effects, immunology)
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Cytokines (immunology, metabolism)
  • Humans
  • Imidazoles (pharmacology, therapeutic use)
  • Immunologic Factors (pharmacology, therapeutic use)
  • Immunotherapy (methods)
  • Macrophages (drug effects, immunology, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms (immunology, metabolism, therapy)
  • Receptors, IgG (immunology, metabolism, physiology)
  • Toll-Like Receptor 7 (agonists, metabolism)
  • Toll-Like Receptor 8 (agonists, metabolism)
  • Tumor Cells, Cultured

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