科研之友
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摘要
Fc gamma receptor (Fc gamma R) 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 Fc gamma R activity within the context of antibody therapy. Human peripheral blood monocytes treated with the TLR2 agonist Pam2CSK4 showed significantly enhanced Fc gamma R-mediated cytokine production as well as phagocytic ability. An examination of the molecular mechanism behind this enhancement revealed increased expression of both Fc gamma RIIa and the common gamma subunit following Pam2CSK4 treatment. Interestingly however, expression of the inhibitory receptor Fc gamma RIIb was also modestly increased. Further investigation revealed that Pam2CSK4 also dramatically decreased the expression of SHIP, the major mediator of Fc gamma RIIb 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 Fc gamma R enhancement was not unique to the diacylated Pam2CSK4, we also tested Pam3CSK4, a related triacylated TLR2 agonist. Results showed significant enhancement in Fc gamma R function and expression. Taken together, these findings indicate that TLR2 activation can positively modulate Fc gamma R and suggest that TLR2 agonists should be considered for testing as adjuvants for antitumor antibody therapy.
- 出版日期2013-4-26
