同位素动态示踪PD-L1/CD47双抗免疫疗法介导CD8+ T细胞肿瘤组织浸润及药效相关性研究

免疫治疗是目前肿瘤治疗的主要策略之一，CD8+ T细胞是肿瘤免疫治疗的主要效应细胞，然而，目前对免疫治疗不同阶段肿瘤浸润CD8+ T细胞的动力学变化情况及驱动机制尚不清楚。传统方法在活体动态监测CD8+ T细胞方面存在挑战。我们前期研究初步建立了核素示踪体内无创实时定量CD8+ T细胞的方法；研究发现靶向CD47/PD-L1双特异抗体的药效优于两种单抗单独使用，且药效作用与治疗过程中肿瘤CD8+ T细胞增加有关。本课题拟选用CD47/PD-L1双特异抗体为工具药，利用核素示踪技术监测其在优化的人源化荷瘤小鼠中的药效学及CD8+ T细胞的浸润动力学，同时分析不同免疫治疗阶段巨噬细胞极化状态、血管正常化及趋化因子等相关指标变化与CD8+ T细胞增加的相关性，有望阐明免疫治疗时CD8+ T细胞增加的驱动力。本项目对肿瘤免疫治疗病人的精准筛选、个体化用药方案设计及早期疗效预测具有重要指导意义。

Tumor immunotherapy is one of the main strategies for cancer treatment. CD8+ T cells are the main effector cells of tumor immunotherapy. However, the dynamic changes and driving mechanisms of tumor-infiltrating CD8+ T cells at different stages of immunotherapy are still unclear. Traditional methods have some challenges in the real-time monitoring of CD8+ T cells in vivo during immunotherapy. Our previous research has initially established a method for non-invasive quantification of CD8+ T cells by radionuclide tracing. We also have found that the efficacy of CD47/PD-L1 bispecific antibody is better than the two monoclonal antibodies used alone, and the efficacy is related to the infiltration of CD8+ T cells in the tumor tissues. In this study, we propose to use the CD47/PD-L1 bispecific antibody as a tool to monitor its pharmacodynamics effects and the infiltration kinetics of CD8+ T cells in optimized humanized tumor-bearing mice using radioisotope tracer molecular imaging techniques. The correlation between the changes of macrophage polarization status, vascular normalization and chemokines and the increase of CD8+ T cells at different stages of immunotherapy will be also analyzed. It is expected to elucidate the driving mechanisms of CD8+ T cells infiltration during immunotherapy. This project has important implications for precise screening, individualized dosing regimen design and early efficacy prediction of tumor immunotherapy patients.