基于JAK/STAT信号通路探讨重离子辐射调控MDSCs及肿瘤免疫应答的机理研究

The discussion of the relationship between radiotherapy and tumor immune response has gradually become a research hotspot in recent years. Myeloid-derived suppressor cells (MDSCs) have immunosuppressive function, which can prevent immune cells such as T lymphocytes from targeting tumors, and the JAK/STAT signaling pathway is the cornerstone for MDSCs to survive and function. Therefore, this project intends to establish a melanoma tumor-bearing mouse model, radiate tumor sites with heavy ions locally, detect the changes of MDSCs after heavy ion irradiation by flow cytometry, and analyze the regulation of JAK/STAT signaling pathway by Western blot, co-immunoprecipitation and other methods. In the end, we try to explain the mechanism of immune response induced by heavy ion radiation through inhibiting of MDSCs. This study provides a new academic viewpoint for the treatment of cancer by heavy ions, and also provides new ideas for the optimization of heavy ion clinical treatment programs.

放射疗法与肿瘤免疫应答之间关系的探讨逐步成为近年来的研究热点。骨髓衍生性抑制细胞（myeloid-derived suppressor cells, MDSCs）具有免疫抑制功能，能够阻止T淋巴细胞等免疫细胞靶向攻击肿瘤，而JAK/STAT信号通路是骨髓衍生性抑制细胞赖以生存和发挥功能的基石。因此，本项目拟建立黑色素瘤荷瘤小鼠模型，采用重离子局部照射肿瘤部位，利用流式细胞技术实现重离子辐射对MDSCs数量变化的检测；通过蛋白质印记、免疫共沉淀等方法分析重离子辐射对JAK/STAT信号通路的调控；最后依据免疫细胞数量的变化阐释重离子辐射通过抑制MDSCs引起免疫应答的机理。本项目旨在通过对MDSCs这座桥梁的研究来揭示重离子辐射引起肿瘤免疫应答的机制，为重离子治癌提供了一种新的学术观点，也为重离子临床治疗方案的优化提供了新的思路。

放射疗法与肿瘤免疫应答之间关系的探讨逐步成为近年来的研究热点。骨髓衍生性抑制细胞（myeloid-derived suppressor cells, MDSCs）具有免疫抑制功能，能够阻止T淋巴细胞等免疫细胞靶向攻击肿瘤，而JAK/STAT信号通路是骨髓衍生性抑制细胞赖以生存和发挥功能的基石。因此，本项目建立了黑色素瘤荷瘤小鼠模型，筛选出最佳照射剂量5Gy，采用重离子局部照射肿瘤部位，利用流式细胞技术实现重离子辐射对MDSCs数量变化的检测，发现重离子降低了荷瘤小鼠骨髓、脾脏、血液和瘤体中MDSCs的所占比率，升高了CD3, CD4, CD8等免疫细胞的比率；通过蛋白质印记、ELISA等方法证明了重离子辐射对JAK/STAT信号通路的负向调控；最后依据免疫细胞数量的变化阐释了重离子辐射通过抑制MDSCs引起免疫应答的机理。另外，我们还将重离子与免疫疗法联合治疗黑色素瘤，发现联合疗法能够显著增强肿瘤的免疫应答水平，降低了肿瘤生长的速率，延长了黑色素瘤荷瘤小鼠的生存时间。项目最终通过对MDSCs这座桥梁的研究揭示了重离子辐射引起肿瘤免疫应答的机制，为重离子治癌提供了一种新的学术观点，也为重离子临床治疗方案的优化提供了新的思路。