Anti-EGFR antibody cetuximab enhances the cytolytic activity of natural killer cells towards osteosarcoma
Menée in vitro, cette étude montre que le cetuximab est susceptible d'améliorer l'efficacité des cellules NK dans le traitement des ostéosarcomes de stade avancé
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 NK cells which can be improved by IL-15 stimulation. In this study, we explored whether the cytolytic function of resting NK cells can be augmented and specifically directed towards sarcoma cells by antibody-dependent cellular cytotoxicity (ADCC). Experimental Design: 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 NK cells from osteosarcoma patients and healthy controls was measured with 4 h 51 Cr release assays. Results: EGFR surface expression was demonstrated on chemotherapy-sensitive and -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 to 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-derived NK cells against autologous tumor cells was as efficient as of NK cells from healthy donors. Conclusion: Our data demonstrate that the cytolytic potential of resting NK cells can be potentiated and directed towards osteosarcoma cells with cetuximab. Therefore, cetuximab-mediated immunotherapy may be considered a novel treatment modality in the management of advanced osteosarcoma.