Abstract
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. 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. 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. 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.
Highlights
Activation of Toll-like receptors (TLR) 7 and 8 by engineered agonists has been shown to aid in combating viruses and tumors
The strength of Fcγ receptor (FcγR) response is largely determined by the ratio of activating (FcγRI, FcγRIIa, FcγRIII, and the γ-subunit) to inhibitory (FcγRIIb) receptors, as mice genetically deleted for FcγRIIb show markedly enhanced antibody-mediated tumor clearance in vivo [4]
When R-848 treatment and FcγR activation were combined, there was a superadditive level of tumor necrosis factor α (TNFα) secretion
Summary
Activation of Toll-like receptors (TLR) 7 and 8 by engineered agonists has been shown to aid in combating viruses and tumors. We wished to test the effect of TLR7/8 activation on monocyte Fcγ receptor (FcγR) function, as they are critical mediators of antibody therapy. Experimental Design: The effect of the TLR7/8 agonist R-848 on cytokine production and antibodydependent 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 FcγR. Murine bone marrow–derived macrophages from WT and knockout mice were examined to determine the downstream pathway involved with regulating FcγR expression. The efficacy of R-848 as an adjuvant for antibody therapy was tested using a CT26-HER2/neu solid tumor model
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