FLASH-RT促进树突状细胞淋巴结归巢及T细胞激活能力的效果及机制研究

如何降低放疗副反应是亟待解决的临床问题，FLASH放疗能实现有效杀死肿瘤细胞的同时显著降低毒性，但其临床应用因缺乏对其生物学效应的充分探索而进展缓慢。申请人前期用DC消耗实验证实了DC在FLASH效应中的重要性。结合FLASH-RT后DC表面共刺激分子表达上调、Th1促炎因子分泌增多、淋巴结归巢能力增强的现象，申请人推测FLASH-RT或许能通过刺激DC的成熟及其淋巴结归巢而增加T细胞激活水平，最终表现为肿瘤控制率的改善和生存的获益。因此，本研究拟通过可视化DC成像平台完成FLASH-RT对树突状细胞淋巴结归巢能力的影响，并深入探讨FLASH-RT是否通过CD40/80/86途径、CCL21/CCR7途径、mDial-RhoA介导的细胞骨架重排途径促进促进DCs成熟、DCs的趋化及向淋巴结迁移，并在引流淋巴结内探究DC-T激活效应。

How to reduce side effects of radiotherapy is an urgent clinical problem. FLASH radiotherapy can effectively kill tumor cells while significantly reducing the toxicity of normal tissues. However, its clinical application has been slow due to the lack of sufficient exploration of its biological effects. We previously used DC depletion experiments to confirm the importance of DCs in FLASH-RT to increase tumor control and improve overall survival. Besides the expression of costimulatory molecules on the surface of DCs was significantly up-regulated, the secretion of Th1 pro-inflammatory factors was significantly increased, and the ability of lymph node homing was enhanced after FLASH-RT. Thus I speculated that FLASH-RT may increase the maturation of DCs and their lymph node homing. The level of T-cell activation ultimately manifests itself in improved tumor control rates and survival benefits. Therefore, this study intends to investigate the effect of FLASH-RT on the lymph node homing of dendritic cells, and deeply explore whether FLASH-RT promotes DCs maturation mediated by CD40/80/86 pathway, promote DCs chemotaxis via CCL21/CCR7 pathway and assist migration to lymph nodes by mDial-RhoA mediated cytoskeletal rearrangement.Furthermore, the DC-T cell interaction in vivo was discussed in detail from the perspective of antigen-specific T cell activation and non-antigen-specific T cell activation to reveal the DCs-related immune effect and molecular mechanism of FLASH-RT.