A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration
Corresponding Author
Thomas K. Hoffmann
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Department of Otorhinolaryngology, University of Essen, Hufelandstr. 55, University of Duisburg-Essen, 45147 Essen, GermanySearch for more papers by this authorKerstin Schirlau
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorEnikö Sonkoly
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorSven Brandau
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorStephan Lang
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorAndor Pivarcsi
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorVera Balz
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorAnja Müller
Department of Radiooncology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorBernhard Homey
Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorEdwin Boelke
Department of Radiooncology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorTorsten Reichert
Department of Maxillofacial Surgery, University of Regensburg, Regensburg, Germany
Search for more papers by this authorUlrike Friebe-Hoffmann
Department of Obstetrics and Gynecology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorJens Greve
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorPatrick Schuler
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorKathrin Scheckenbach
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorJörg Schipper
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorMurat Bas
Department of Otorhinolaryngology, Technical University of Munich, Munich, Germany
Search for more papers by this authorTheresa L. Whiteside
Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorHenning Bier
Department of Otorhinolaryngology, Technical University of Munich, Munich, Germany
Search for more papers by this authorCorresponding Author
Thomas K. Hoffmann
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Department of Otorhinolaryngology, University of Essen, Hufelandstr. 55, University of Duisburg-Essen, 45147 Essen, GermanySearch for more papers by this authorKerstin Schirlau
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorEnikö Sonkoly
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorSven Brandau
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorStephan Lang
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorAndor Pivarcsi
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorVera Balz
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorAnja Müller
Department of Radiooncology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorBernhard Homey
Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorEdwin Boelke
Department of Radiooncology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorTorsten Reichert
Department of Maxillofacial Surgery, University of Regensburg, Regensburg, Germany
Search for more papers by this authorUlrike Friebe-Hoffmann
Department of Obstetrics and Gynecology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorJens Greve
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorPatrick Schuler
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorKathrin Scheckenbach
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorJörg Schipper
Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany
Search for more papers by this authorMurat Bas
Department of Otorhinolaryngology, Technical University of Munich, Munich, Germany
Search for more papers by this authorTheresa L. Whiteside
Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorHenning Bier
Department of Otorhinolaryngology, Technical University of Munich, Munich, Germany
Search for more papers by this authorAbstract
Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). Monoclonal antibodies (mAbs) against EGFR are currently used for therapy of recurrent or metastatic disease; however, their mode of action is not completely understood. To investigate the immunological effects of anti-EGFR mAb, we generated a three-dimensional spheroid model of EGFR-expressing SCCHN and used this model to study the effect of anti-EGFR mAb on leukocyte migration toward tumors. Pretreatment with the blocking anti-EGFR mAb EMD 72000, its F(ab′)2 fragments or an EGFR tyrosine kinase inhibitor led to substantially increased leukocyte infiltration into EGFR overexpressing tumor spheroids, but not into those with low EGFR expression. Nonblocking anti-EGFR mAb or fibroblast-specific mAb did not affect leukocyte infiltration, suggesting that the observed increase in leukocyte infiltration depends on interference with EGFR activation. Using a human cytokine macroarray, we demonstrated that the blockade of EGFR by anti-EGFR mAb in EGFR-overexpressing SCCHN cells leads to differential expression of several cytokines and chemokines, including the chemokine MCP-1/CCL-2. The significant upregulation of MCP-1/CCL2 on exposure to anti-EGFR mAb was confirmed by quantitative PCR and enzyme-linked immunospot analyses. Moreover, blocking anti-MCP-1 antibody inhibited leukocyte migration toward tumor cells induced by anti-EGFR mAb, pointing to an important role of MCP-1/CCL2 in anti-EGFR mAb-induced leukocyte migration. Our findings demonstrate that anti-EGFR mAb induces leukocyte infiltration to tumor spheroids by upregulating chemokine expression. This novel mechanism for anti-EGFR mAb action may contribute to the antitumor effects of anti-EGFR mAb in vivo. © 2009 Wiley-Liss, Inc.
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