title: Cetuximab-mediated tumor regression depends on innate and adaptive immune responses.
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.
authors.affiliation: Center for Infection and Immunity and National Key Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xuanming
authors.initials: X
authors.lastname: Yang
authors.forename: Xunmin
authors.initials: X
authors.lastname: Zhang
authors.forename: Eric D
authors.initials: ED
authors.lastname: Mortenson
authors.forename: Olga
authors.initials: O
authors.lastname: Radkevich-Brown
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000068818:Cetuximab; D018899:CpG Islands; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D066246:ErbB Receptors; D000068818:Cetuximab