Chemotherapy-resistant osteosarcoma is highly susceptible to IL-15-activated allogeneic and autologous NK cells

• DOI: 10.1007/s00262-010-0965-3
• Publication Date: 2011-01-14T12:32:10Z
• Authors: Emilie P. Buddingh; Marco W. Schilham; S. Eriaty N. Ruslan; Dagmar Berghuis; Karoly Szuhai; Jolien Suurmond; Antonie H. M. Tam...; Hans Gelderblom; R. Maarten Egeler; Massimo Serra; Pancras C. W. Hog...; Arjan C. Lankester
• Keywords: Antigens, Differentiation, T-Lymphocyte; Cytotoxicity, Immunologic; Cancer Research; Immunology; Bone Neoplasms; Cell Separation; Lymphocyte Activation; Immunotherapy, Adoptive; 03 medical and health sciences; 0302 clinical medicine; Immunology and Allergy; Humans; Cells, Cultured; Interleukin-15; Osteosarcoma; Flow Cytometry; Immunohistochemistry; 3. Good health; Killer Cells, Natural; Oncology; Drug Resistance, Neoplasm; NK Cell Lectin-Like Receptor Subfamily K; Tissue Array Analysis; Original Article

High-grade osteosarcoma occurs predominantly in adolescents and young adults and has an overall survival rate of about 60%, despite chemotherapy and surgery. Therefore, novel treatment modalities are needed to prevent or treat recurrent disease. Natural killer (NK) cells are lymphocytes with cytotoxic activity toward virus-infected or malignant cells. We explored the feasibility of autologous and allogeneic NK cell-mediated therapies for chemotherapy-resistant and chemotherapy-sensitive high-grade osteosarcoma. The expression by osteosarcoma cells of ligands for activating NK cell receptors was studied in vitro and in vivo, and their contribution to NK cell-mediated cytolysis was studied by specific antibody blockade. Chromium release cytotoxicity assays revealed chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines and osteosarcoma primary cultures to be sensitive to NK cell-mediated cytolysis. Cytolytic activity was strongly enhanced by IL-15 activation and was dependent on DNAM-1 and NKG2D pathways. Autologous and allogeneic activated NK cells lysed osteosarcoma primary cultures equally well. Osteosarcoma patient-derived NK cells were functionally and phenotypically unimpaired. In conclusion, osteosarcoma cells, including chemoresistant variants, are highly susceptible to lysis by IL-15-induced NK cells from both allogeneic and autologous origin. Our data support the exploitation of NK cells or NK cell-activating agents in patients with high-grade osteosarcoma.