Cetuximab-induced natural killer cell cytotoxicity in head and neck squamous cell carcinoma cell lines: investigation of the role of cetuximab sensitivity and HPV status

• Published in: British journal of cancer Vol. 123; no. 5; pp. 752 - 761
• Main Authors: Baysal, Hasan, De Pauw, Ines, Zaryouh, Hannah, De Waele, Jorrit, Peeters, Marc, Pauwels, Patrick, Vermorken, Jan Baptist, Smits, Evelien, Lardon, Filip, Jacobs, Julie, Wouters, An
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2020; Nature Publishing Group
• Subjects: 631/250/2504/2506; 692/4028/67/1059/2326; 692/4028/67/1059/602; 692/4028/67/1536; Antibody-Dependent Cell Cytotoxicity - drug effects; Antineoplastic Agents, Immunological - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Growth Processes - drug effects; Cell Line, Tumor; Cetuximab - pharmacology; Cytotoxicity; Drug Resistance; Epidemiology; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - immunology; ErbB Receptors - metabolism; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - virology; Human papillomavirus; Humans; Hypoxia; Immune response; Immunoglobulins; Immunotherapy; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Molecular Medicine; Monoclonal antibodies; Natural killer cells; Oncology; Papillomaviridae - isolation & purification; Papillomavirus Infections - immunology; Papillomavirus Infections - pathology; Signal transduction; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - immunology; Squamous Cell Carcinoma of Head and Neck - pathology; Squamous Cell Carcinoma of Head and Neck - virology; Targeted cancer therapy; Tumor cell lines; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0934-3

Background
The epidermal growth factor receptor (EGFR) is overexpressed by 80–90% of squamous cell carcinoma of head and neck (HNSCC). In addition to inhibiting EGFR signal transduction, cetuximab, a monoclonal antibody targeting EGFR can also bind to fragment crystallisable domain of immunoglobulins G1 present on natural killer (NK), causing antibody-dependent cellular cytotoxicity (ADCC). However, presence of cetuximab resistance limits effective clinical management of HNSCC.
Methods
In this study, differences in induction of ADCC were investigated in a panel of ten HNSCC cell lines. Tumour cells were co-cultured with NK cells and monitored using the xCELLigence RTCA.
Results
While ADCC was not influenced by HPV status, hypoxia and cetuximab resistance did affect ADCC differentially. Intrinsic cetuximab-resistant cell lines showed an increased ADCC induction, whereas exposure to hypoxia reduced ADCC. Baseline EGFR expression was not correlated with ADCC. In contrast, EGFR internalisation following cetuximab treatment was positively correlated with ADCC.
Conclusion
These findings support the possibility that resistance against cetuximab can be overcome by NK cell-based immune reactions. As such, it provides an incentive to combine cetuximab with immunotherapeutic approaches, thereby possibly enhancing the anti-tumoural immune responses and achieving greater clinical effectiveness of EGFR-targeting agents.