1. Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity.
- Author
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Elavazhagan S, Fatehchand K, Santhanam V, Fang H, Ren L, Gautam S, Reader B, Mo X, Cheney C, Briercheck E, Vasilakos JP, Dietsch GN, Hershberg RM, Caligiuri M, Byrd JC, Butchar JP, and Tridandapani S
- Subjects
- Amino Acid Chloromethyl Ketones pharmacology, Angiotensinogen genetics, Angiotensinogen metabolism, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents pharmacology, Blotting, Western, Cells, Cultured, Cetuximab, Cluster Analysis, Dose-Response Relationship, Drug, Granzymes antagonists & inhibitors, Granzymes genetics, Humans, Imidazoles pharmacology, Interleukin-2 genetics, Interleukin-2 metabolism, Monocytes cytology, Monocytes drug effects, NF-kappa B genetics, NF-kappa B metabolism, Oligonucleotide Array Sequence Analysis, Perforin genetics, Perforin metabolism, Quinolines pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Thiazoles pharmacology, Time Factors, Toll-Like Receptor 8 agonists, Transcriptome drug effects, Antibody-Dependent Cell Cytotoxicity, Granzymes metabolism, Monocytes metabolism, Toll-Like Receptor 8 metabolism
- 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., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
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