Cetuximab-mediated tumor regression depends on innate and adaptive immune responses

Mol Ther. 2013 Jan;21(1):91-100. doi: 10.1038/mt.2012.184. Epub 2012 Sep 18.


Epidermal growth factor receptor (EGFR) over-signaling leads to more aggressive tumor growth. The antitumor effect of Cetuximab, an anti-EGFR antibody, depends on oncogenic-signal blockade leading to tumor cell apoptosis and antibody dependent cell-mediated cytotoxicity (ADCC). However, whether adaptive immunity plays a role in Cetuximab-mediated tumor inhibition is unclear, as current xenograft models lack adaptive immunity and human-EGFR-dependent mouse tumor cell lines are unavailable. Using a newly developed xenograft model with reconstituted immune cells, we demonstrate that the Cetuximab effect becomes more pronounced and reduces the EGFR(+) human tumor burden when adaptive immunity is present. To further study this in a mouse tumor model, we created a novel EGFR(+) mouse tumor cell line and demonstrated that Cetuximab-induced tumor regression depends on both innate and adaptive immunity components, including CD8(+) T cells, MyD88, and FcγR. To test whether strong innate signals inside tumor tissues amplifies the Cetuximab-mediated therapeutic effect, Cetuximab was conjugated to CpG. This conjugate is more potent than Cetuximab alone for complete tumor regression and resistance to tumor rechallenge. Furthermore, Cetuximab-CpG conjugates can activate tumor-reactive T cells for tumor regression by increasing dendritic cell (DC) cross-presentation. Therefore, this study establishes new models to evaluate immune responses induced by antibody-based treatment, defines molecular mechanisms, and provides new tumor-regression strategies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cetuximab
  • CpG Islands
  • Enzyme-Linked Immunosorbent Assay
  • ErbB Receptors / antagonists & inhibitors*
  • Humans
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / immunology
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Membrane Glycoproteins
  • Receptors, Interleukin-1
  • TIRAP protein, human
  • ErbB Receptors
  • Cetuximab