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Immuntherapie von Kopf-Hals-Karzinomen

Identifizierung eines neuartigen Wirkungsmechanismus von Anti-EGFR-Antikörpern

Immunotherapy of head and neck cancer

Identification of a novel mechanism for anti-EGFR mAb anti-tumor effects

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Zusammenfassung

Durch die Überexpression des epidermalen Wachstumsfaktor-Rezeptors (EGFR) in fast allen Plattenepithelkarzinomen des Kopf-Hals-Bereichs (PKH) steht ein attraktives Zielmolekül für die Applikation von spezifischen Antikörpern (AK) zur Verfügung. Die AK-Therapie ist für PKH mit Rezidiv oder Metastasen zugelassen, wenngleich ihre genaue Wirkungsweise nur teilweise bekannt ist. Um das immunologische Wirkprinzip der AK zu erfassen, wurde ein dreidimensionales Tumormodell (Sphäroide) aus PKH mit dem Ziel entwickelt, eine durch Anti-EGFR-AK induzierte Leukozyteninfiltration zu untersuchen. Die AK-Blockade von EGFR führte zur differenziellen Expression (cDNA-Makroarray) von verschiedenen Chemokinen und Zytokinen, insbesondere des „monocyte chemotactic protein 1“ (MCP-1/CCL-2). Bestätigt wurde die durch Anti-EGFR-AK induzierte Hochregulation von MCP-1 durch Polymerasekettenreaktion (PCR) und ELISPOT-Technik, eine funktionelle Relevanz durch einen blockierenden Anti-MCP-1-AK. Die hier nachgewiesene chemokininduzierte Leukozyteninfiltration in dreidimensionale PKH-Sphäroide dürfte zumindest teilweise für die antitumorale Wirkung von Anti-EGFR-AK in vivo verantwortlich sein.

Abstract

The epidermal growth factor receptor (EGFR) is found to be overexpressed in nearly all squamous cell carcinomas of the head and neck (SCCHN). Monoclonal antibodies (mAbs) against EGFR are currently used to treat recurrent or metastatic disease; however, their mode of action is not fully understood. To investigate the immunological effects of anti-EGFR mAb, a three-dimensional spheroid model of EGFR-expressing SCCHN was generated and used to study the effect of anti-EGFR mAb on leukocyte migration towards tumors. The blockade of EGFR by anti-EGFR mAb in EGFR-overexpressing SCCHN cells led to differential expression (array) of several cytokines and chemokines, including the chemokine MCP-1/CCL-2. This was confirmed by quantitative PCR and ELISPOT analyses and shown to be functionally relevant by blocking experiments. These findings demonstrate that anti-EGFR mAb induces leukocyte infiltration to tumor spheroids by up-regulating chemokine expression. This novel mechanism for anti-EGFR mAb action may contribute to the anti-tumor effects of anti-EGFR mAb in vivo.

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Literatur

  1. Baselga J, Pfister D, Cooper MR et al (2000) Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904–914

    PubMed  CAS  Google Scholar 

  2. Balló H, Koldovsky P, Hoffmann T et al (1999) Establishment and characterization of four cell lines derived from human head and neck squamous cell carcinomas for an autologous tumor-fibroblast in vitro model. Anticancer Res 19:3827–3836

    PubMed  Google Scholar 

  3. Bergler W, Bier H, Ganzer U (1989) The expression of epidermal growth factor receptors in the oral mucosa of patients with oral cancer. Arch Otorhinolaryngol 246:121–125

    Article  PubMed  CAS  Google Scholar 

  4. Bier H, Reiffen KA, Haas I, Stasiecki P (1995) Dose-dependent access of murine anti-epidermal growth factor receptor monoclonal antibody to tumor cells in patients with advanced laryngeal and hypopharyngeal carcinoma. Eur Arch Otorhinolaryngol 252:433–439

    Article  PubMed  CAS  Google Scholar 

  5. Bier H, Hoffmann T (1996) Epidermal growth factor receptor in head and neck squamous cell carcinomas. In: Werner JA, Lippert BM, Rudert HH (Hrsg) Head and neck cancer – advances in basic research. Excerpta Medica Int. Congress Series 1114:225–234

    CAS  Google Scholar 

  6. Bier H, Hoffmann T, Lierop A van (1998) Anti-(epidermal growth factor) receptor monoclonal antibodies for the induction of antibody-dependent cell-mediated cytotoxicity against squamous cell carcinoma lines of the head and neck. Cancer Immunol Immunother 46:167–173

    Article  PubMed  CAS  Google Scholar 

  7. Bier H, Hoffmann T, Hauser U et al (2001) Clinical trial with escalating doses of the anti-epidermal growth factor receptor humanized monoclonal antibody EMD 72000 in patients with advanced squamous cell carcinoma of the larynx and hypopharynx. Cancer Chemother Pharmacol 47:519–524

    Article  PubMed  CAS  Google Scholar 

  8. Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578

    Article  PubMed  CAS  Google Scholar 

  9. Bonner JA, Harari PM, Giralt J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28

    Article  PubMed  CAS  Google Scholar 

  10. Christensen ME, Therkildsen MH, Hansen BL et al (1992) Epidermal growth factor receptor expression on oral mucosa dysplastic epithelia and squamous cell carcinomas. Eur Arch Otorhinolaryngol 249:243–247

    Article  PubMed  CAS  Google Scholar 

  11. Fan Z, Baselga J, Masui H, Mendelsohn J (1993) Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637–4642

    PubMed  CAS  Google Scholar 

  12. Gires O, Münz M, Schaffrik M et al (2004) Profile identification of disease-associated humoral antigens using AMIDA, a novel proteomics-based technology. Cell Mol Life Sci 61:1198–1207

    Article  PubMed  CAS  Google Scholar 

  13. Grandis JR, Melhem MF, Gooding WE (1998) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90:824–832

    Article  Google Scholar 

  14. Hoffmann T, Hafner D, Ballo H et al (1997) Antitumor activity of anti-epidermal growth factor receptor monoclonal antibodies and cisplatin in ten human head and neck squamous cell carcinoma lines. Anticancer Res 17:4419–4425

    PubMed  CAS  Google Scholar 

  15. Hoffmann TK, Balló H, Braunstein S et al (2001) Serum level and tissue expression of c-erbB-1 and c-erbB-2 proto-oncogene products in patients with squamous cell carcinoma of the head and neck. Oral Oncol 37:50–56

    Article  PubMed  CAS  Google Scholar 

  16. Hoffmann TK, Bier H, Whiteside TL (2004) Targeting the immune system: novel therapeutic approaches in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 53:1055–1067

    Article  PubMed  Google Scholar 

  17. Hoffmann TK, Whiteside TL, Bier H (2005) Squamous cell carcinoma of the head and neck. Principles and current concepts of immunotherapy. HNO 53:285–297

    Article  PubMed  CAS  Google Scholar 

  18. Hoffmann TK, Schirlau K, Sonkoly E et al (2009) A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration. Int J Cancer 124:2589–2596

    Article  PubMed  CAS  Google Scholar 

  19. Köhler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497

    Article  PubMed  Google Scholar 

  20. Liu B, Fang M, Schmidt M et al (2000) Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer 82:1991–1999

    Article  PubMed  CAS  Google Scholar 

  21. Mendelsohn J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787–2799

    Article  PubMed  CAS  Google Scholar 

  22. Milas L, Mason K, Hunter N (2000) In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6:701–708

    PubMed  CAS  Google Scholar 

  23. Monji M, Senju S, Nakatsura T et al (2002) Head and neck cancer antigens recognized by the humoral immune system. Biochem Biophys Res Commun 294:734–741

    Article  PubMed  CAS  Google Scholar 

  24. Petit AM, Rak J, Hung MC et al (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523–1530

    PubMed  CAS  Google Scholar 

  25. Robert F, Ezekiel MP, Spencer SA et al (2001) Phase I study of anti–epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 19:3234–3243

    PubMed  CAS  Google Scholar 

  26. Türeci O, Sahin U, Schobert I et al (1996) The SSX-2 gene, which is involved in the t(X;18) translocation of synovial sarcomas, codes for the human tumor antigen HOM-MEL-40. Cancer Res 56:4766–4772

    PubMed  Google Scholar 

  27. Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127

    Article  PubMed  CAS  Google Scholar 

  28. Wu X, Rubin M, Fan Z (1996) Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene 12:1397–1403

    PubMed  CAS  Google Scholar 

  29. Zeidler R, Reisbach G, Wollenberg B et al (1999) Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. J Immunol 163:1246–1252

    PubMed  CAS  Google Scholar 

  30. Zenner HP (1981) Monoclonal antibodies against surface antigens of laryngeal carcinoma cells. Eur Arch Otorhinolaryngol 233:161–172

    Article  CAS  Google Scholar 

  31. Zenner HP, Herrmann IF, Moser L (1986) Monoclonal antibody UW 21/123: clinical use and diagnostic specificity in head and neck cancers. Laryngol Rhinol Otol 65:287–291

    Article  CAS  Google Scholar 

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  1. Hals-Nasen-Ohren-Universitätsklinik Essen, Hufelandstraße 55, 45147, Essen, Deutschland

    T.K. Hoffmann

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Correspondence to T.K. Hoffmann.

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Diese Arbeit erhielt auf der 81. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e. V. 2010 den Anton-von-Tröltsch-Preis 2010.

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Hoffmann, T. Immuntherapie von Kopf-Hals-Karzinomen. HNO 59, 224–229 (2011). https://doi.org/10.1007/s00106-010-2251-2

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