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A Mechanism of Resistance to Antibody-Targeted Immune Attack

Dalal S Aldeghaither1,2, David J Zahavi1, Joseph C Murray3

  • 1Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia.

Cancer Immunology Research
|December 20, 2018
PubMed

Insights

Cancer patients often resist monoclonal antibody therapy. This study reveals that resistance to antibody-dependent cell-mediated cytotoxicity (ADCC) involves reduced target cell adhesion and immune synapse formation, offering insights into overcoming treatment failure.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Targeted monoclonal antibody therapy is a key cancer treatment.
  • Antibody-dependent cell-mediated cytotoxicity (ADCC) is a critical mechanism for antibody efficacy.
  • Therapeutic resistance limits patient responses to monoclonal antibody treatments.

Purpose of the Study:

  • To investigate the mechanisms of immune resistance in cancer therapy.
  • To develop a model system for studying resistance to antibody-dependent cell-mediated cytotoxicity (ADCC).
  • To identify cellular and molecular changes associated with ADCC resistance.

Main Methods:

  • Continuous exposure of epidermal growth factor receptor (EGFR)-positive A431 cells to cetuximab and NK92-CD16V effector cells.
  • Generation of ADCC-resistant (ADCCR1) and ADCC-sensitive (ADCCS1) cell lines.
  • Analysis of gene expression, cell-surface molecule expression, and immune cell activation.

Main Results:

  • ADCC-resistant cells exhibited reduced EGFR expression and failed to activate NK cells.
  • Resistance was linked to overexpression of histone- and interferon-related genes.
  • Development of resistance involved decreased expression of cell-surface molecules crucial for immune synapse formation.
  • Resistance mechanisms did not involve epithelial-to-mesenchymal transition or classic immune checkpoints.

Conclusions:

  • ADCC resistance is induced by genetic and epigenetic changes.
  • Resistance leads to a loss of target cell adhesion, impairing immune synapse formation and NK cell activation.
  • Understanding these resistance mechanisms is crucial for improving cancer immunotherapy outcomes.

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