Cetuximab-mediated Tumor Regression Depends on Innate and Adaptive Immune Responses
| Autor: | Xunmin Zhang, Yang Xin Fu, Eric D. Mortenson, Olga Radkevich-Brown, Yang Wang, Xuanming Yang |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cetuximab
Enzyme-Linked Immunosorbent Assay Adaptive Immunity CD8-Positive T-Lymphocytes Biology Antibodies Monoclonal Humanized Mice 03 medical and health sciences 0302 clinical medicine Immune system Neoplasms Drug Discovery Genetics medicine Animals Humans Epidermal growth factor receptor Molecular Biology 030304 developmental biology Pharmacology Antibody-dependent cell-mediated cytotoxicity Mice Inbred BALB C 0303 health sciences Membrane Glycoproteins Antibody-Dependent Cell Cytotoxicity Receptors Interleukin-1 Dendritic cell Acquired immune system Xenograft Model Antitumor Assays digestive system diseases 3. Good health ErbB Receptors 030220 oncology & carcinogenesis Immunology Cancer research biology.protein Molecular Medicine Original Article CpG Islands Antibody CD8 Signal Transduction T-Lymphocytes Cytotoxic medicine.drug |
| Zdroj: | Molecular Therapy. 21:91-100 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2012.184 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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