title: Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity.
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.
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors: Saranya
authors: S
authors: Elavazhagan
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors: Kavin
authors: K
authors: Fatehchand
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors: Vikram
authors: V
authors: Santhanam
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors: Huiqing
authors: H
authors: Fang
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors: Li
authors: L
authors: Ren
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors: Shalini
authors: S
authors: Gautam
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors: Brenda
authors: B
authors: Reader
authors: Center for Biostatistics, The Ohio State University, Columbus, OH 43210;
authors: Xiaokui
authors: X
authors: Mo
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors: Carolyn
authors: C
authors: Cheney
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors: Edward
authors: E
authors: Briercheck
authors: 3M Drug Delivery Systems Division, St. Paul, MN 55144; and.
authors: John P
authors: JP
authors: Vasilakos
authors: VentiRx Pharmaceuticals, Seattle, WA 98101.
authors: Gregory N
authors: GN
authors: Dietsch
authors: VentiRx Pharmaceuticals, Seattle, WA 98101.
authors: Robert M
authors: RM
authors: Hershberg
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors: Michael
authors: M
authors: Caligiuri
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors: John C
authors: JC
authors: Byrd
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; tridandapani.2@osu.edu butchar.2@osu.edu.
authors: Jonathan P
authors: JP
authors: Butchar
authors: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; tridandapani.2@osu.edu butchar.2@osu.edu.
authors: Susheela
authors: S
authors: Tridandapani
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D000068818:Cetuximab; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C551788:CL 075; D007093:Imidazoles; D007376:Interleukin-2; D016328:NF-kappa B; C510468:PRF1 protein, human; D011804:Quinolines; C495349:TLR8 protein, human; D013844:Thiazoles; D051200:Toll-Like Receptor 8; C440223:Z-Ala-Ala-Asp-chloromethylketone; D000808:Angiotensinogen; D054353:Perforin; D053804:Granzymes; D000068818:Cetuximab; C402365:resiquimod