Abstract
FcγRs are critical mediators of mAb cancer therapies, because they drive cytotoxic processes upon binding of effector cells to opsonized targets. Along with NK cells, monocytes are also known to destroy Ab-coated targets via Ab-dependent cellular cytotoxicity (ADCC). However, the precise mechanisms by which monocytes carry out this function have remained elusive. In this article, we show that human monocytes produce the protease granzyme B upon both FcγR and TLR8 activation. Treatment with TLR8 agonists elicited granzyme B and also enhanced FcγR-mediated granzyme B production in an additive fashion. Furthermore, monocyte-mediated ADCC against cetuximab-coated tumor targets was enhanced by TLR8 agonist treatment, and this enhancement of ADCC required granzyme B. Hence we have identified granzyme B as an important mediator of FcγR function in human monocytes and have uncovered another mechanism by which TLR8 agonists may enhance FcγR-based therapies.
Highlights
In an effort to understand in greater depth the biologic effects of TLR7 and TLR8 agonists on monocytes within the context of FcgR signaling, we found that TLR8, but not TLR7, agonists elicited the production of granzyme B
We examined the effects of TLR7 versus TLR8 agonists on monocyte activation
Other findings support this, showing that NK cells lyse Ab-coated targets within 4 h [25, 53], but measurable levels of Ab-dependent cellular cytotoxicity (ADCC) by monocytes/ macrophages might be seen only after as long as 18 h [22, 54]. Despite this difference in time required for ADCC between cell types, we have shown that monocytes, much like NK cells, use granzyme B for ADCC
Summary
Monocyte-mediated ADCC against cetuximab-coated tumor targets was enhanced by TLR8 agonist treatment, and this enhancement of ADCC required granzyme B. Granzyme B production represents a novel mechanism by which monocyte FcgR can target Ab-coated tumor cells, and this can be enhanced through the use of TLR8-selective agonists. To verify that the differences seen were qualitative and quantitative, we identified differential expression of transcripts upregulated uniquely by TLR7 agonist treatment in PBMs from additional donors including protein kinase C a, kinase suppressor of Ras 1, and MAPK 1 (Supplemental Fig. 2A–C).
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