Abstract
Fcγ receptor (FcγR) clustering on monocytes/macrophages results in phagocytosis and inflammatory cytokine production, which serve to eliminate antibody-opsonized targets and activate neighboring immune cells. Toll-like receptor 2 (TLR2), which recognizes a range of both bacterial and fungal components, elicits strong proinflammatory responses in these cells when stimulated by ligands, either natural or synthetic. Thus, we explored the possibility that TLR2 agonists could strengthen FcγR activity within the context of antibody therapy. Human peripheral blood monocytes treated with the TLR2 agonist Pam2CSK4 showed significantly enhanced FcγR-mediated cytokine production as well as phagocytic ability. An examination of the molecular mechanism behind this enhancement revealed increased expression of both FcγRIIa and the common γ subunit following Pam2CSK4 treatment. Interestingly however, expression of the inhibitory receptor FcγRIIb was also modestly increased. Further investigation revealed that Pam2CSK4 also dramatically decreased the expression of SHIP, the major mediator of FcγRIIb inhibitory activity. Using a murine Her2/neu solid tumor model of antibody therapy, we found that Pam2CSK4 significantly enhanced the ability of anti-Her2 antibody to reduce the rate of tumor growth. To verify that the FcγR enhancement was not unique to the diacylated Pam2CSK4, we also tested Pam3CSK4, a related triacylated TLR2 agonist. Results showed significant enhancement in FcγR function and expression. Taken together, these findings indicate that TLR2 activation can positively modulate FcγR and suggest that TLR2 agonists should be considered for testing as adjuvants for antitumor antibody therapy.
Highlights
Toll-like receptors recognize bacterial components, leading to immune activation
We found that the Toll-like receptor 2 (TLR2) agonist Pam2CSK4 enhanced Fc␥ receptor (Fc␥R)-mediated cytokine production as well as phagocytic ability
These results suggest that TLR2 activation is an effective means of strengthening monocyte Fc␥R expression and function and that such agonists could be further examined as potential adjuvants for antitumor antibody therapy
Summary
Toll-like receptors recognize bacterial components, leading to immune activation. Results: TLR2 ligands alter monocyte/macrophage Fc␥R and phosphatase expression to improve function both in vitro and in vivo. Fc␥ receptor (Fc␥R) clustering on monocytes/macrophages results in phagocytosis and inflammatory cytokine production, which serve to eliminate antibody-opsonized targets and activate neighboring immune cells. Human peripheral blood monocytes treated with the TLR2 agonist Pam2CSK4 showed significantly enhanced Fc␥R-mediated cytokine production as well as phagocytic ability. Results showed significant enhancement in Fc␥R function and expression Taken together, these findings indicate that TLR2 activation can positively modulate Fc␥R and suggest that TLR2 agonists should be considered for testing as adjuvants for antitumor antibody therapy. Among the immune effector cells, monocytes/macrophages play a critical role in that they directly attack opsonized targets and release a variety of chemokines and cytokines that can attract and activate neighboring cells (6 – 8). Purified and/or synthetic TLR agonists such as CpG (for TLR9), imiquimod (for TLR7), flagellin (for TLR5), Pam3CSK4 (for TLR2), and others continue to be evaluated, with many showing promise toward treating asthma, cancer, and viral infections and for strengthening vaccine responses [10]
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