以CD47为靶点的吞噬检查点抑制剂在骨肉瘤治疗中的应用及机制研究

骨肉瘤是儿童及青少年最常见的恶性骨肿瘤，患者预后较差。目前主要的治疗手段是新辅助化疗+手术切除，除一线化疗药物外，无其它有效治疗方法是如今骨肉瘤治疗面临的瓶颈。近年来，实体肿瘤的免疫治疗取得突破性进展，主要包括以PD-1、CTLA-4为靶点的T细胞免疫检查点抑制剂，但在骨肉瘤中并未取得显著疗效。我们前期针对骨肉瘤免疫微环境的研究中发现，PD-L1在骨肉瘤患者中的表达率为35.48%(22/62)，略低于其它间叶源性肿瘤表达；相比于T细胞浸润数量，在骨肉瘤中肿瘤相关巨噬细胞TAM浸润更加显著，这提示骨肉瘤中巨噬细胞介导的免疫反应可能占据更为重要的地位。因此本项目在前期工作基础上将系统的探究巨噬细胞吞噬检查点CD47在骨肉瘤细胞免疫逃逸中的作用，开展动物实验和临床实验探索CD47单抗在骨肉瘤治疗中的可行性及其分子机制，为骨肉瘤免疫治疗新方向的开拓提供理论和临床基础。

Osteosarcoma is the most common malignant bone tumor in children and adolescents. At present, the main treatment is neoadjuvant chemotherapy plus surgical resection. Apart from the first-line chemotherapy drugs, no other effective treatment is the bottleneck of osteosarcoma treatment. In recent years, breakthroughs have been made in tumor immunotherapy, including T cell immunosuppressive checkpoint inhibitors targeting at PD-1 and CTLA-4, and macrophage phagocytic checkpoint inhibitors targeting at CD47. In our previous study on the immune microenvironment of osteosarcoma, PD-L1 was found to be 35.48% (22 / 62), slightly lower than that of other mesenchymal tumors; compared with the number of T cell infiltration, Tam infiltration of tumor-related macrophages was more significant in osteosarcoma, suggesting that macrophage mediated immune response may play a more important role in osteosarcoma. Therefore, on the basis of previous work, this project will systematically explore the role of macrophage phagocytosis checkpoint CD47 in the immune escape of osteosarcoma cells, carry out animal experiments and clinical experiments to explore the feasibility and molecular mechanism of monoclonal antibody CD47 in the treatment of osteosarcoma, and provide theoretical and clinical basis for the development of new direction of osteosarcoma immunotherapy.