Granzyme B Expression Is Enhanced in Human Monocytes by TLR8 Agonists and Contributes to Antibody-Dependent Cellular Cytotoxicity
| Autor: | John P. Vasilakos, Kavin Fatehchand, Huiqing Fang, Shalini Gautam, Jonathan P. Butchar, Saranya Elavazhagan, Brenda F. Reader, Xiaokui Mo, Robert M. Hershberg, Gregory N. Dietsch, Vikram Santhanam, John C. Byrd, Michael A. Caligiuri, Carolyn Cheney, Li Ren, Susheela Tridandapani, Edward L. Briercheck |
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| Rok vydání: | 2015 |
| Předmět: |
Granzyme B production
Time Factors medicine.drug_class Blotting Western Immunology Angiotensinogen Cetuximab Antineoplastic Agents Antibodies Monoclonal Humanized Monoclonal antibody Granzymes Monocytes Article Amino Acid Chloromethyl Ketones medicine Cluster Analysis Humans Immunology and Allergy Cytotoxic T cell Cells Cultured Oligonucleotide Array Sequence Analysis Antibody-dependent cell-mediated cytotoxicity Dose-Response Relationship Drug biology Perforin Reverse Transcriptase Polymerase Chain Reaction Antibody-Dependent Cell Cytotoxicity Imidazoles NF-kappa B NFKB1 Granzyme B Thiazoles Granzyme Toll-Like Receptor 8 Quinolines Cancer research biology.protein Interleukin-2 Antibody Transcriptome |
| Zdroj: | The Journal of Immunology. 194:2786-2795 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Fcγ receptors (FcγR) are critical mediators of monoclonal antibody cancer therapies, as they drive cytotoxic processes upon binding of effector cells to opsonized targets. Along with natural killer (NK) cells, monocytes are also known to destroy antibody-coated targets via antibody-dependent cellular cytotoxicity (ADCC). However, the precise mechanisms by which monocytes carry out this function have remained elusive. Here, we show that human monocytes produce the protease Granzyme B upon both FcγR and Toll-like Receptor (TLR) 8 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. |
| Databáze: | OpenAIRE |
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