TLR2 ligands modulate Fcγ receptor expression and function in monocytes (P4397)

Abstract

Abstract Fcγ receptor (FcγR) clustering on monocytes/macrophages leads to phagocytosis, cytokine release and other responses designed to clear the antibody-opsonized targets. Toll-like Receptor 2 activation elicits strong proinflammatory responses, so we explored the possibility that ligands for TLR2 could indirectly strengthen FcγR activity. We treated human peripheral blood monocytes (PBM) with the TLR2 agonist Pam2CSK4 and found significantly enhanced FcγR-mediated cytokine production and phagocytosis. Further examination showed that the agonist increased the mRNA and protein levels of FcγRIIa and the common γ-subunit. Interestingly however, the inhibitory receptor FcγRIIb was also upregulated. We also found a concurrent decrease in SHIP and an increase in miR-155, which may help explain the enhanced FcγR function despite upregulated inhibitory FcγRIIb. Next, using a murine Her2/neu solid-tumor model of antibody therapy we found that Pam2CSK4 significantly enhanced antibody-mediated reduction of tumor growth, although the effects were not superadditive. Finally, we tested whether the effect was acylation-specific by treating PBM with the tri-acylated Pam3CSK4 and measuring FcγR expression and function. Results showed that Pam3CSK4 was equally effective at all dosages tested. Collectively, these findings show that TLR2 ligands can positively modulate FcγR expression and function, and hence may warrant further investigation as putative adjuvants for antitumor antibody therapy.