An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells

Cancer Cell. 2011 Jan 18;19(1):101-13. doi: 10.1016/j.ccr.2010.11.012.

Abstract

Antibodies to cell-surface antigens trigger activatory Fcγ receptor (FcγR)-mediated retrograde signals in leukocytes to control immune effector functions. Here, we uncover an FcγR mechanism that drives antibody-dependent forward signaling in target cells. Agonistic antibodies to death receptor 5 (DR5) induce cancer-cell apoptosis and are in clinical trials; however, their mechanism of action in vivo is not fully defined. Interaction of the DR5-agonistic antibody drozitumab with leukocyte FcγRs promoted DR5-mediated tumor-cell apoptosis. Whereas the anti-CD20 antibody rituximab required activatory FcγRs for tumoricidal function, drozitumab was effective in the context of either activatory or inhibitory FcγRs. A CD40-agonistic antibody required similar FcγR interactions to stimulate nuclear factor-κB activity in B cells. Thus, FcγRs can drive antibody-mediated receptor signaling in target cells.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism*
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Apoptosis / immunology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • CD40 Antigens / agonists
  • CD40 Antigens / immunology
  • Cell Line, Tumor
  • Female
  • HCT116 Cells
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology
  • Immunoglobulin G / pharmacology
  • Killer Cells, Natural / immunology
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / genetics
  • Mutation / immunology
  • Myeloid Cells / immunology
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Polymorphism, Single Nucleotide / genetics
  • Polymorphism, Single Nucleotide / immunology
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Receptor Aggregation / immunology
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / immunology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Signal Transduction / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • CD40 Antigens
  • Fcgr2b protein, mouse
  • Fcgr3 protein, mouse
  • Fcgr4 protein, mouse
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • NF-kappa B
  • Receptors, IgG
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • apomab
  • drozitumab