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

70 Scopus citations

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 2013

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Cetuximab-mediated tumor regression depends on innate and adaptive immune responses'. Together they form a unique fingerprint.

  • Cite this