FcγRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck

Rodney J. Taylor, Siaw Lin Chan, Aaron Wood, Caroline J. Voskens, Jeffrey S. Wolf, Wei Lin, Andrei Chapoval, Dan H. Schulze, Guoliang Tian, Scott E. Strome

Research output: Contribution to journalArticle

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Abstract

Purpose: The interaction of Fc fragments of antibodies with the Fcγ receptors is an essential checkpoint in antibody-dependent cellular cytotoxicity (ADCC). Specific polymorphisms at position 158 enhance FcγRIIIa affinity for IgG1 and are associated with improved clinical outcome in lymphoma patients treated with IgG1 anti-CD20 antibody. The role of ADCC in the therapeutic effects of the α-epidermal growth factor receptor (EGFR) mAb, cetuximab, in patients with squamous cell carcinoma of the head and neck (SCCHN) is poorly defined. We employed three SCCHN cell lines to test two hypotheses: (1) SCCHN is susceptible to cetuximab-mediated ADCC, (2) efficacy of ADCC is associated with polymorphisms at position 158 of FcγRIIIa. Experimental design: FcγRIIIa-158 polymorphisms were determined for healthy donors, and their purified NK cells were used as effector cells against three SCCHN cell lines in ADCC assays. Cytotoxicity levels were compared for each polymorphism class. Proliferation and cell cycle assays were done to examine the direct effects of cetuximab. Results: Our results indicate that SCCHN is susceptible to cetuximab-mediated ADCC in vitro. NK cytotoxic efficiency correlates with donor 158-polymorphisms in FcγRIIIa. Overall cytotoxicity was greatest for individuals having a single V allele when compared to homozygous F/F individuals; the cumulative percent cytotoxicity for each polymorphism among the cell lines was 58.2% V/V, 50.6% V/F, and 26.1% F/F (P < 0.001). Additionally, the presence of a V allele correlated with superior natural cytotoxicity against NK sensitive targets. Conclusion: These data have both prognostic and therapeutic relevance and support the design of a prospective trial to determine the influence of FcγRIIIa polymorphisms on the clinical outcome of patients with SCCHN treated with α-EGFR mAbs.

Original languageEnglish (US)
Pages (from-to)997-1006
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume58
Issue number7
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

Fingerprint

Antibodies
Epidermal Growth Factor Receptor
Cell Line
Immunoglobulin G
Alleles
Tissue Donors
Immunoglobulin Fc Fragments
Fc Receptors
Therapeutic Uses
Carcinoma, squamous cell of head and neck
Cetuximab
Natural Killer Cells
Anti-Idiotypic Antibodies
Lymphoma
Cell Cycle
Research Design
Therapeutics

Keywords

  • ADCC
  • Cetuximab
  • NK
  • Polymorphisms
  • SCCHN

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Taylor, R. J., Chan, S. L., Wood, A., Voskens, C. J., Wolf, J. S., Lin, W., ... Strome, S. E. (2009). FcγRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. Cancer Immunology, Immunotherapy, 58(7), 997-1006. https://doi.org/10.1007/s00262-008-0613-3

FcγRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. / Taylor, Rodney J.; Chan, Siaw Lin; Wood, Aaron; Voskens, Caroline J.; Wolf, Jeffrey S.; Lin, Wei; Chapoval, Andrei; Schulze, Dan H.; Tian, Guoliang; Strome, Scott E.

In: Cancer Immunology, Immunotherapy, Vol. 58, No. 7, 01.07.2009, p. 997-1006.

Research output: Contribution to journalArticle

Taylor, RJ, Chan, SL, Wood, A, Voskens, CJ, Wolf, JS, Lin, W, Chapoval, A, Schulze, DH, Tian, G & Strome, SE 2009, 'FcγRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck', Cancer Immunology, Immunotherapy, vol. 58, no. 7, pp. 997-1006. https://doi.org/10.1007/s00262-008-0613-3
Taylor, Rodney J. ; Chan, Siaw Lin ; Wood, Aaron ; Voskens, Caroline J. ; Wolf, Jeffrey S. ; Lin, Wei ; Chapoval, Andrei ; Schulze, Dan H. ; Tian, Guoliang ; Strome, Scott E. / FcγRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. In: Cancer Immunology, Immunotherapy. 2009 ; Vol. 58, No. 7. pp. 997-1006.
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AU - Chan, Siaw Lin

AU - Wood, Aaron

AU - Voskens, Caroline J.

AU - Wolf, Jeffrey S.

AU - Lin, Wei

AU - Chapoval, Andrei

AU - Schulze, Dan H.

AU - Tian, Guoliang

AU - Strome, Scott E.

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AB - Purpose: The interaction of Fc fragments of antibodies with the Fcγ receptors is an essential checkpoint in antibody-dependent cellular cytotoxicity (ADCC). Specific polymorphisms at position 158 enhance FcγRIIIa affinity for IgG1 and are associated with improved clinical outcome in lymphoma patients treated with IgG1 anti-CD20 antibody. The role of ADCC in the therapeutic effects of the α-epidermal growth factor receptor (EGFR) mAb, cetuximab, in patients with squamous cell carcinoma of the head and neck (SCCHN) is poorly defined. We employed three SCCHN cell lines to test two hypotheses: (1) SCCHN is susceptible to cetuximab-mediated ADCC, (2) efficacy of ADCC is associated with polymorphisms at position 158 of FcγRIIIa. Experimental design: FcγRIIIa-158 polymorphisms were determined for healthy donors, and their purified NK cells were used as effector cells against three SCCHN cell lines in ADCC assays. Cytotoxicity levels were compared for each polymorphism class. Proliferation and cell cycle assays were done to examine the direct effects of cetuximab. Results: Our results indicate that SCCHN is susceptible to cetuximab-mediated ADCC in vitro. NK cytotoxic efficiency correlates with donor 158-polymorphisms in FcγRIIIa. Overall cytotoxicity was greatest for individuals having a single V allele when compared to homozygous F/F individuals; the cumulative percent cytotoxicity for each polymorphism among the cell lines was 58.2% V/V, 50.6% V/F, and 26.1% F/F (P < 0.001). Additionally, the presence of a V allele correlated with superior natural cytotoxicity against NK sensitive targets. Conclusion: These data have both prognostic and therapeutic relevance and support the design of a prospective trial to determine the influence of FcγRIIIa polymorphisms on the clinical outcome of patients with SCCHN treated with α-EGFR mAbs.

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