TY - JOUR
T1 - Cetuximab-mediated tumor regression depends on innate and adaptive immune responses
AU - Yang, Xuanming
AU - Zhang, Xunmin
AU - Mortenson, Eric D.
AU - Radkevich-Brown, Olga
AU - Wang, Yang
AU - Fu, Yang Xin
N1 - Funding Information:
We thank William Pao (Vanderbilt-Ingram Cancer Center) for plasmid DNA encoding human EGFR. This research was in part supported by US National Institutes of Health grants CA134563 and CA97296 to Y.X.F. The authors declared no conflict of interest.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
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U2 - 10.1038/mt.2012.184
DO - 10.1038/mt.2012.184
M3 - Article
C2 - 22990672
AN - SCOPUS:84871922121
SN - 1525-0016
VL - 21
SP - 91
EP - 100
JO - Molecular Therapy
JF - Molecular Therapy
IS - 1
ER -