基于实时监测肿瘤免疫微环境状态的放射免疫联用策略及其机制研究

免疫检查点疗法是当前最受关注的肿瘤治疗新方法，但仅少部分患者长期获益。放疗可增敏肿瘤免疫治疗，但其兼具影响免疫反应的正反机制，所以两者如何进行高效联合仍有很多争议。放疗可以影响肿瘤的免疫微环境，如PDL1表达和免疫细胞的浸润与功能；它们也是影响肿瘤免疫治疗效果的主要因素。最近研究表明肿瘤血管的灌注功能与T细胞的活性相关，此外，我们设计合成了可临床转化的 PDL1 PET显像剂。据此，我们提出探索基于可视化监测肿瘤免疫微环境的新型放射免疫联合治疗策略。本项目将建立实时检测放射影响肿瘤组织PDL1整体表达水平的方法，分析放疗过程中肿瘤血管灌注功能与T细胞浸润和活性的相关性，进而建立高效的放射免疫协同治疗方案，并研究其作用机理。本项目的顺利完成将建立一种全新的基于实时监测在体PDL1整体表达水平和血管功能状态的肿瘤精准放射免疫联用策略，为临床应用奠定理论基础。

Immune checkpoint blockade therapy has become a new standard treatment modality for many types of cancer, but only achieves long-term survival benefit in a small percentage of cancer patients. Radiotherapy exhibits both promoting and suppressing effects on cancer immunotherapy, thus the optimal combination of radiotherapy and immunotherapy remain elusive. Radiotherapy influences the expression of PDL1 and the status of tumor-infiltrating immune cells, which plays crucial roles in cancer immunotherapy. Recent studies suggest that improved vessel perfusion is positively correlated with the activities of T cells. In addition, we developed a translational PET imaging agent for PDL1. Therefore, we proposed to explore a novel radio-immunotherapy according to the real-time monitoring of the status of the tumor immune microenvironment. We will establish a real-time imaging method to analyze the effect of radiotherapy on the overall expression levels of PDL1 using PET scan, develop a non-invasive approach to evaluate the status of tumor-infiltrating T cells via measuring the tumor vessel perfusion upon radiotherapy, and then explore an optimal strategy to combine radiotherapy with cancer immunotherapy and to investigate the underlying mechanism. The successful completion of this project may develop a novel noninvasive strategy to stratify patients for precision radio-immunotherapy based on the visualization of the overall expression levels of PDL1 and real-time tumor vascular function, thus providing a theoretical base to upgrate radio-immunotherapy in the clinic.