Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity

J Immunol. 2015 Mar 15;194(6):2786-95. doi: 10.4049/jimmunol.1402316. Epub 2015 Feb 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Angiotensinogen / genetics
  • Angiotensinogen / metabolism
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibody-Dependent Cell Cytotoxicity*
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cells, Cultured
  • Cetuximab
  • Cluster Analysis
  • Dose-Response Relationship, Drug
  • Granzymes / antagonists & inhibitors
  • Granzymes / genetics
  • Granzymes / metabolism*
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • 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
  • Toll-Like Receptor 8 / metabolism*
  • Transcriptome / drug effects

Substances

  • Amino Acid Chloromethyl Ketones
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • CL 075
  • Imidazoles
  • Interleukin-2
  • NF-kappa B
  • PRF1 protein, human
  • Quinolines
  • TLR8 protein, human
  • Thiazoles
  • Toll-Like Receptor 8
  • Z-Ala-Ala-Asp-chloromethylketone
  • Angiotensinogen
  • Perforin
  • Granzymes
  • Cetuximab
  • resiquimod

Associated data

  • GEO/GSE64480