Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
Cancer Immunol Immunother. 2011 Apr;60(4):575-86. doi: 10.1007/s00262-010-0965-3. Epub 2011 Jan 15.
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.
高级骨肉瘤主要发生在青少年和年轻成年人中，尽管进行了化疗和手术，总体生存率仍约为 60%。因此，需要新的治疗方法来预防或治疗复发性疾病。自然杀伤 (NK) 细胞是具有针对病毒感染或恶性细胞的细胞毒性活性的淋巴细胞。我们探索了自体和同种异体 NK 细胞介导的疗法治疗化疗耐药和化疗敏感的高级骨肉瘤的可行性。我们研究了骨肉瘤细胞体外和体内表达激活 NK 细胞受体的配体的情况，并通过特异性抗体阻断研究了它们对 NK 细胞介导的细胞溶解的贡献。铬释放细胞毒性测定显示，化疗敏感和化疗耐药骨肉瘤细胞系和骨肉瘤原代培养物对 NK 细胞介导的细胞溶解敏感。IL-15 激活强烈增强了细胞溶解活性，并且依赖于 DNAM-1 和 NKG2D 途径。自体和同种异体激活的 NK 细胞同样有效地溶解骨肉瘤原代培养物。骨肉瘤患者来源的 NK 细胞在功能和表型上均未受损。总之，包括耐药变体在内的骨肉瘤细胞对来自异体和自体来源的 IL-15 诱导的 NK 细胞的溶解非常敏感。我们的数据支持在高级骨肉瘤患者中利用 NK 细胞或 NK 细胞激活剂。
