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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Authors: | Andrés López-Albaitero Steve C Lee Sarah Morgan Jennifer R Grandis William E Gooding Soldano Ferrone " target="_blank">Robert L Ferris |
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Institution: | (1) Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA;(2) Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA;(3) Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;(4) Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;(5) Department of Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;(6) Cancer Immunology, Immunotherapy and Immunoprevention Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;(7) The Hillman Cancer Center Research Pavilion, 5117 Centre Avenue, Room 2.26b, Pittsburgh, PA 15213, USA; |
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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.
An erratum to this article can be found at |
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Keywords: | EGFR Antibodies ADCC Immunotherapy |
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