High-grade osteosarcoma is a malignant bone tumor with the highest incidence in young patients. In chapter 2, we studied MSCs of osteosarcoma patients and found downregulation of HCLS1 in... Show moreHigh-grade osteosarcoma is a malignant bone tumor with the highest incidence in young patients. In chapter 2, we studied MSCs of osteosarcoma patients and found downregulation of HCLS1 in osteosarcoma patient derived MSCs as compared to healthy donor derived MSCs. Despite almost two years in culture, none of the samples underwent spontaneous transformation. An increase in binucleation was noted upon increasing passage in both osteosarcoma patient and healthy donor derived MSCs. In chapter 3, prognostic factors related to the survival of patients with pulmonary metastasized high-grade osteosarcoma were studied. Higher metastatic tumor burden (i.e. larger number of pulmonary nodules), presence of vital metastases upon resection and male sex were associated with an increased risk of death. In chapter 4 we show that osteosarcoma metastasis seems to be inhibited by the presence of macrophages in the tumor microenvironm ent. In chapters 5 and 6 we show that osteosarcoma cells are sensitive to lysis by both autologous and allogeneic NK cells. Patient derived NK cells can be adequately activated by cytokine treatment with IL-15 (chapter 5) or IFN-_ (chapter 6). Therefore, activation of autologous NK cells (either in vivo or ex vivo) may be efficacious. In conclusion, the activation of innate immune cells such as macrophages and NK cells is a promising new adjuvant treatment strategy to treat patients with high-grade osteosarcoma Show less
Osteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic... Show moreOsteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic or chemotherapy-resistant disease have a poor outcome. Thus, novel targeted therapies are needed that combine potent and specific anti-cancer activity with limited toxicity toward normal tissues. The thesis is introduced by an outline of the biological properties of osteosarcoma and Ewing sarcoma, followed by an overview of cancer immunology and immunotherapy with the primary focus on innate immunity of human natural killer (NK) cells and macrophages. In the research chapters, cellular interactions of NK cells and macrophages with bone tumor cells are characterized in order to achieve favorable effects on anti-cancer immune cell functions. It is demonstrated that the anti-cancer potential of especially NK cells but also macrophages can be enhanced and directed to the bone tumor cells. It is discussed that the modulation of tumor__immune cell interactions may help to design novel immunotherapeutic approaches to harness anti-cancer functions of innate immune cells against osteosarcoma and Ewing sarcoma. Show less
