Anti-EGFR antibody cetuximab enhances the cytolytic activity of natural killer cells toward osteosarcoma

Jens H W Pahl, S. Eriaty N Ruslan, Emilie P. Buddingh, Susy J. Santos, Karoly Szuhai, Massimo Serra, Hans Gelderblom, Pancras C W Hogendoorn, R. Maarten Egeler, Marco W. Schilham, Arjan C. Lankester

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Purpose: Osteosarcoma and Ewing's sarcoma are the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease have a poor prognosis, illustrating the need for alternative therapies. Sarcoma cells are susceptible to the cytolytic activity of resting natural killer (NK) cells which can be improved by interleukin (IL)-15 stimulation. In this study, we explored whether the cytolytic function of resting NK cells can be augmented and specifically directed toward sarcoma cells by antibody-dependent cellular cytotoxicity (ADCC). Experimental Design: Epidermal growth factor receptor (EGFR) expression was examined on osteosarcoma and Ewing's sarcoma cell lines by flow cytometry and in osteosarcoma biopsy and resection specimens by immunohistochemistry. Cetuximab-mediated ADCC by NKcells from osteosarcoma patients and healthy controls was measured with 4-hour 51Cr release assays. Results: EGFR surface expression was shown on chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cells (12/12), most primary osteosarcoma cultures (4/5), and few Ewing's sarcoma cell lines (2/7). In the presence of cetuximab, the cytolytic activity of resting NK cells against all EGFR-expressing sarcoma cells was substantially increased and comparable with that of IL-15-activated NK cells. Surface EGFR expression on primary osteosarcoma cultures correlated with EGFR expression in the original tumor. The cytolytic activity of osteosarcoma patient-derivedNKcells against autologous tumor cells was as efficient as that of NK cells from healthy donors. Conclusion: Our data show that the cytolytic potential of resting NK cells can be potentiated and directed toward osteosarcoma cells with cetuximab. Therefore, cetuximab-mediated immunotherapy may be considered a novel treatment modality in the management of advanced osteosarcoma.

Original languageEnglish
Pages (from-to)432-441
Number of pages10
JournalClinical Cancer Research
Issue number2
Publication statusPublished - Jan 15 2012

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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