Skip to main content

Advertisement

SpringerLink
Log in

Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

An Erratum to this article was published on 18 June 2009

Abstract

Immunotherapy with the EGFR-specific mAb cetuximab is clinically effective in 10–20% of patients with squamous cell carcinoma of the head and neck (SCCHN). Little information is available about the mechanism(s) underlying patients’ differential clinical response to cetuximab-based immunotherapy, although this information may contribute to optimizing the design of cetuximab-based immunotherapy. Our understanding of these mechanisms would benefit from the characterization of the variables which influence the extent of cell dependent-lysis of SCCHN cells incubated with cetuximab in vitro. Therefore, in this study we have investigated the role of FcγR IIIa-158 genotype expressed by effector NK cells, cetuximab concentration, and EGFR expression level by SCCHN cells in the extent of their in vitro lysis and in the degree of NK cell activation. PBMC or purified CD56+ NK cells genotyped at IIIa codon 158 and SCCHN cell lines expressing different levels of EGFR have been used as effectors and targets, respectively, in antibody dependent cellular cytotoxicity (ADCC) assays. Furthermore, supernatants from ADCC assays were analyzed for cytokine and chemokine levels using multiplexed ELISA. We found that the extent of lysis of SCCHN cells was influenced by the EGFR expression level, cetuximab concentration, and FcγR polymorphism. Effector cells expressing the FcγR IIIa-158 VV allele were significantly (P < 0.0001) more effective than those expressing FcγR IIIa VF and VV alleles in mediating lysis of SCCHN cells expressed higher levels of the activation markers CD69 and CD107a, and secreted significantly (P < 0.05) larger amounts of inflammatory cytokines and chemokines. IL-2 or IL-15 treatment increased cetuximab-mediated ADCC by poor binding FcγR IIIa 158 FF expressing NK cells. The importance of the FcγR IIIa-158 polymorphism in cytotoxicity of SCCHN cells by NK cells supports a potential role for immune activation and may explain patient variability of cetuximab mediated clinical responses. Cellular and secreted immune profiles and FcγR genotypes from patients’ lymphocytes may provide clinically useful biomarkers of immune activation in cetuximab treated patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ang KK, Berkey BA, Tu X et al (2002) Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62(24):7350–7356

    PubMed  CAS  Google Scholar 

  2. Grandis JR, Tweardy DJ (1993) Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 53(15):3579–3584

    PubMed  CAS  Google Scholar 

  3. 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(6):567–578

    Article  PubMed  CAS  Google Scholar 

  4. Vermorken JB, Mesia R, Vega-Villegas ME et al (eds) (2006) Cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R&M SCCHN) (EXTREME). In: ASCO annual meeting proceedings, part I, vol 24

  5. Taylor C, Hershman D, Shah N et al (2007) Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin Cancer Res 13(17):5133–5143

    Article  PubMed  CAS  Google Scholar 

  6. Varchetta S, Gibelli N, Oliviero B et al (2007) Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res 67(24):11991–11999

    Article  PubMed  CAS  Google Scholar 

  7. Zhang W, Gordon M, Schultheis AM et al (2007) FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 25(24):3712–3718

    Article  PubMed  CAS  Google Scholar 

  8. Lin CJ, Grandis JR, Carey TE et al (2007) Head and neck squamous cell carcinoma cell lines: established models and rationale for selection. Head Neck 29(2):163–188

    Article  PubMed  Google Scholar 

  9. Thomas SM, Zeng Q, Epperly MW et al (2004) Abrogation of head and neck squamous cell carcinoma growth by epidermal growth factor receptor ligand fused to pseudomonas exotoxin transforming growth factor alpha-PE38. Clin Cancer Res 10(20):7079–7087

    Article  PubMed  CAS  Google Scholar 

  10. Hathaway B, Landsittel DP, Gooding W et al (2005) Multiplexed analysis of serum cytokines as biomarkers in squamous cell carcinoma of the head and neck patients. Laryngoscope 115(3):522–527

    Article  PubMed  CAS  Google Scholar 

  11. Lopez-Albaitero A, Ferris RL (2007) Immune activation by epidermal growth factor receptor specific monoclonal antibody therapy for head and neck cancer. Arch Otolaryngol Head Neck Surg 133(12):1277–1281

    Article  PubMed  Google Scholar 

  12. 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(13):3234–3243

    PubMed  CAS  Google Scholar 

  13. Sok JC, Coppelli FM, Thomas SM et al (2006) Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 12(17):5064–5073

    Article  PubMed  CAS  Google Scholar 

  14. Kalyankrishna S, Grandis JR (2006) Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 24(17):2666–2672

    Article  PubMed  CAS  Google Scholar 

  15. Musolino A, Naldi N, Bortesi B et al (2008) Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 26(11):1789–1796

    Article  PubMed  CAS  Google Scholar 

  16. Weng WK, Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21(21):3940–3947

    Article  PubMed  CAS  Google Scholar 

  17. Roda JM, Joshi T, Butchar JP et al (2007) The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clin Cancer Res 13(21):6419–6428

    Article  PubMed  CAS  Google Scholar 

  18. Dall’Ozzo S, Tartas S, Paintaud G et al (2004) Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration–effect relationship. Cancer Res 64(13):4664–4669

    Article  PubMed  Google Scholar 

  19. Cartron G, Dacheux L, Salles G et al (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99(3):754–758

    Article  PubMed  CAS  Google Scholar 

  20. Mitrovic Z, Aurer I, Radman I, Ajdukovic R, Sertic J, Labar B (2007) FCgammaRIIIA and FCgammaRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B cell lymphoma. Haematologica 92(7):998–999

    Article  PubMed  CAS  Google Scholar 

  21. Lu Y, Li X, Liang K et al (2007) Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. Cancer Res 67(17):8240–8247

    Article  PubMed  CAS  Google Scholar 

  22. Wild R, Fager K, Flefleh C et al (2006) Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels. Mol Cancer Ther 5(1):104–113

    Article  PubMed  CAS  Google Scholar 

  23. Psyrri A, Egleston B, Weinberger P et al (2008) Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray. Cancer Epidemiol Biomarkers Prev 17(6):1486–1492

    Article  PubMed  CAS  Google Scholar 

  24. Kawaguchi Y, Kono K, Mimura K, Sugai H, Akaike H, Fujii H (2007) Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma. Int J Cancer 120(4):781–787

    Article  PubMed  CAS  Google Scholar 

  25. Kurai J, Chikumi H, Hashimoto K et al (2007) Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 13(5):1552–1561

    Article  PubMed  CAS  Google Scholar 

  26. Aerts HJ, Dubois L, Hackeng TM et al (2007) Development and evaluation of a cetuximab-based imaging probe to target EGFR and EGFRvIII. Radiother Oncol 83(3):326–332

    Article  PubMed  CAS  Google Scholar 

  27. Yang W, Wu G, Barth RF et al (2008) Molecular targeting and treatment of composite EGFR and EGFRvIII-positive gliomas using boronated monoclonal antibodies. Clin Cancer Res 14(3):883–891

    Article  PubMed  CAS  Google Scholar 

  28. Patel D, Lahiji A, Patel S et al (2007) Monoclonal antibody cetuximab binds to and down-regulates constitutively activated epidermal growth factor receptor vIII on the cell surface. Anticancer Res 27(5A):3355–3366

    PubMed  CAS  Google Scholar 

  29. Linkov F, Lisovich A, Yurkovetsky Z et al (2007) Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling. Cancer Epidemiol Biomarkers Prev 16(1):102–107

    Article  PubMed  CAS  Google Scholar 

  30. Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL (2004) Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Cancer Res 10(11):3755–3762

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work has been funded by a pilot grant from the American Head and Neck Society (ALA and RLF) and R01 DE19727 (RLF).

Author information

Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA

    Andrés López-Albaitero, Steve C. Lee, Sarah Morgan, Jennifer R. Grandis & Robert L. Ferris

  2. Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA

    Jennifer R. Grandis

  3. Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    William E. Gooding

  4. Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Soldano Ferrone

  5. Department of Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Soldano Ferrone & Robert L. Ferris

  6. Cancer Immunology, Immunotherapy and Immunoprevention Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Soldano Ferrone & Robert L. Ferris

  7. The Hillman Cancer Center Research Pavilion, 5117 Centre Avenue, Room 2.26b, Pittsburgh, PA, 15213, USA

    Robert L. Ferris

Authors
  1. Andrés López-Albaitero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steve C. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer R. Grandis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William E. Gooding
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Soldano Ferrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert L. Ferris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert L. Ferris.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00262-009-0726-3

Rights and permissions

Reprints and permissions

About this article

Cite this article

López-Albaitero, A., Lee, S.C., Morgan, S. et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother 58, 1853–1862 (2009). https://doi.org/10.1007/s00262-009-0697-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-009-0697-4

Keywords

Search

Navigation