Direct and antibody-dependent cell-mediated cytotoxicity of head and neck squamous cell carcinoma cells by high-affinity natural killer cells

Oral Oncol. 2019 Mar:90:38-44. doi: 10.1016/j.oraloncology.2019.01.017. Epub 2019 Feb 1.


High affinity natural killer cells (haNKs) are a cell therapy product capable of mediating both direct and antibody-dependent cell-mediated cytotoxicity (ADCC). These cells may be particularly useful in tumors that escape T-cell anti-tumor immunity by harboring antigen processing and presentation defects. Here, we demonstrated that haNKs directly kill both HPV-positive and negative head and neck squamous cell carcinoma cells. Variable tumor cell sensitivity to haNK direct cytotoxicity did not correlated with MHC class I chain-related protein A or B (MICA or MICB) expression. Importantly, haNK killing was significantly enhanced via ADCC mediated by cetuximab or avelumab in cells with higher baseline EGFR or PD-L1 expression, respectively. The ability of IFNγ to induce tumor cell PD-L1 expression correlated with enhanced PD-L1-specific ADCC. IFNγ induced neither tumor cell EGFR expression nor EGFR-specific ADCC. Although a single dose of 8 Gy IR did not appear to directly enhance susceptibility to haNK killing alone, enhanced PD-L1- and EGFR-mediated ADCC after IR correlated with increased PD-L1 and EGFR expression in one of four models. This pre-clinical evidence supports the investigation of haNK cellular therapy in combination with ADCC-mediating mAbs, with or without IR, in the clinical trial setting for patients with advanced HNSCCs. Given the MHC-unrestricted nature of this treatment, it may represent an opportunity to treat patients with non-T-cell inflamed tumors.

Keywords: ADCC; Avelumab; Cetuximab; Head and neck cancer; Radiation; haNK.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adoptive Transfer / methods
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • Antibody-Dependent Cell Cytotoxicity / radiation effects
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Cell Survival / radiation effects
  • Cetuximab / therapeutic use
  • Combined Modality Therapy / methods
  • ErbB Receptors / metabolism
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / therapy
  • Humans
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Papillomaviridae / metabolism
  • Radiation, Ionizing
  • Signal Transduction / radiation effects
  • Squamous Cell Carcinoma of Head and Neck / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Squamous Cell Carcinoma of Head and Neck / therapy


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • B7-H1 Antigen
  • CD274 protein, human
  • IFNG protein, human
  • Interferon-gamma
  • EGFR protein, human
  • ErbB Receptors
  • avelumab
  • Cetuximab