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

Xuanming Yang, Xunmin Zhang, Eric D. Mortenson, Olga Radkevich-Brown, Yang Wang, Yang Xin Fu

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)91-100
Number of pages10
JournalMolecular Therapy
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2013

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Adaptive Immunity
Innate Immunity
Epidermal Growth Factor Receptor
Neoplasms
Tumor Cell Line
Heterografts
Cetuximab
Cross-Priming
Antibody-Dependent Cell Cytotoxicity
T-Lymphocytes
Therapeutic Uses
Tumor Burden
Dendritic Cells
Antibody Formation
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Cetuximab-mediated tumor regression depends on innate and adaptive immune responses. / Yang, Xuanming; Zhang, Xunmin; Mortenson, Eric D.; Radkevich-Brown, Olga; Wang, Yang; Fu, Yang Xin.

In: Molecular Therapy, Vol. 21, No. 1, 01.01.2013, p. 91-100.

Research output: Contribution to journalArticle

Yang, X, Zhang, X, Mortenson, ED, Radkevich-Brown, O, Wang, Y & Fu, YX 2013, 'Cetuximab-mediated tumor regression depends on innate and adaptive immune responses', Molecular Therapy, vol. 21, no. 1, pp. 91-100. https://doi.org/10.1038/mt.2012.184
Yang, Xuanming ; Zhang, Xunmin ; Mortenson, Eric D. ; Radkevich-Brown, Olga ; Wang, Yang ; Fu, Yang Xin. / Cetuximab-mediated tumor regression depends on innate and adaptive immune responses. In: Molecular Therapy. 2013 ; Vol. 21, No. 1. pp. 91-100.
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