正电子淋巴造影监测PD-1抗体联合放射治疗远隔效应对转移淋巴结的协同作用

Immunotherapy based on the immune escape mechanism of tumors has disadvantage of low efficiency and large individual differences, which is considered to be related to the complicated microenvironment of tumors. Radiation can not only destroy and disturb tumor microenvironment, but also has ‘abscopal effect’, which will act on primary tumor and metastasis at the same time via releasing tumor-associated antigens and activating tumor-specific T cells. However, tumor immune escape mechanism limits the role of radiation ‘abscopal effect’. Nuclear medicine imaging has the unique advantage of evaluating molecular biological changes of tumors during therapy. Positron lymphography using 18F-FDG was successfully performed in tumor-bearing and normal mice. Significantly prolonged retention of activity was evident in metastatic nodes as compared to normal nodes and inflammatory nodes. This finding enlightens us to try 18F-FLT for lymphography to evaluate the proliferative ability of metastatic lymph nodes. A lymph node metastasis of malignant melanoma mouse model will be established to investigate the synergistic effect of immunological checkpoint inhibitor anti-PD-1 antibody combined with radiation "abscopal effect" on metastatic lymph nodes. The feasibility and superiority of 18F-FDG,18F-FLT PET lymphography for evaluation the efficacy of metastatic lymph nodes will also be studied.

基于肿瘤免疫逃逸机制的免疫疗法，存在有效率低、个体差异大的缺点，这被认为与肿瘤错综复杂的微环境有关。放射治疗不仅能够破坏、扰乱原发灶肿瘤微环境，还具有“远隔效应”，即释放肿瘤相关抗原、激活T细胞免疫，使未被照射的转移灶也缩小。然而肿瘤免疫逃逸特性限制了放疗“远隔效应”发挥作用。皮内注射小分子18F-FDG被发现可用于鼠淋巴通路造影，通过显像剂滞留时间和摄取亮度可鉴别转移淋巴结、正常淋巴结和炎性淋巴结，启迪我们是否能够应用18F-FLT进行正电子淋巴造影，监测转移淋巴结的治疗反应。本项目拟建立鼠恶性黑色素瘤淋巴结转移模型，探讨免疫检查点抑制剂PD-1抗体与原发灶放疗“远隔效应”对转移淋巴结的协同治疗作用；同时研究皮内注射18F-FDG、18F-FLT进行PET淋巴造影监测转移淋巴结治疗反应的可行性和优越性。

基于肿瘤免疫逃逸机制的免疫疗法，存在有效率低、个体差异大的缺点，这被认为与肿瘤错综复杂的微环境有关。放射治疗不仅能够破坏、扰乱原发灶肿瘤微环境，还具有“远隔效应”，即释放肿瘤相关抗原、激活T细胞免疫，使未被照射的转移灶也缩小。然而肿瘤免疫逃逸特性限制了放疗“远隔效应”发挥作用。本项目构建鼠肿瘤淋巴结转移模型，探讨免疫检查点抑制剂PD-1抗体与原发灶放疗“远隔效应”对转移淋巴结的协同治疗作用；采用正电子淋巴造影早期、动态、实时监测转移淋巴结在免疫治疗、放射治疗过程中的变化，结合病理及流式细胞仪免疫细胞浸润检测结果，评估免疫治疗与放射治疗联合应用对转移淋巴结的效果及机制。结果显示PD-1抗体联合原发灶放疗能明显抑制转移淋巴结的增长，其机制与两者联合治疗上调转移淋巴结中CD8+T细胞浸润有关，正电子淋巴结造影可实时动态、简单有效的监测转移淋巴结治疗效果。本项目为多发转移的晚期癌症患者治疗策略及评估手段提供新思路。