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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

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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.

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Acknowledgments

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

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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

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  1. Andrés López-Albaitero
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  2. Steve C. Lee
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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

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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

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

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