基于PD-L1分子影像学特征筛选结直肠癌免疫治疗生物学标志物和构建诊断预测模型

Molecular imaging with antibodies as a probe is a new method for noninvasive dynamic detection of colorectal cancer. Immune checkpoint PD-1/PD-L1 is an important mechanism of tumor tolerance in colorectal cancer. Precise monitoring of PD-L1 expression level in tumor tissues is helpful for the selection of targeted immunotherapy for patients and timely evaluation of efficacy and prognosis. Our group successfully prepared optical imaging agent NIR-PD-L1-mAb and detected the expression of PD-L1 in different colorectal cancer cells and animal models. On this basis, PD-L1 antibody PET and Cerenkov optical molecular probes were prepared using radionuclide 89Zr and 131I, respectively, to detect the dynamic changes of PD-L1 expression in colorectal cancer. The correlation between PD-L1 molecular imaging and immunotherapy response was studied based on the SUV value, immune infiltration, lymphocyte distribution, cytokine levels and mutation frequencies and expression levels of immune-related genes in 18F-FDG of tumor tissues. Based on Naive Bayesian Algorithm, a comprehensive prediction model of prognosis and treatment response was built, and a medical imaging auxiliary diagnosis platform for screening biomarkers relative to colorectal cancer PD-L1 immunotherapy based on molecular imaging features, which is helpful for seletion of patients immunotherapy and clinicians to develop precise treatment strategies.

以抗体为探针的分子影像学检查是结直肠癌无创动态检测的新方法。免疫检测点PD-1/PD-L1是结直肠癌肿瘤耐受的重要机制。在肿瘤组织中精准监测PD-L1有助于免疫治疗选择、疗效及预后评估。课题组前期已成功制备光学显像剂NIR-PD-L1-mAb，检测到不同结直肠癌细胞及动物模型中PD-L1的表达变化。在此基础上，将采用放射性核素89Zr及131I分别制备PD-L1抗体PET与切伦科夫光学分子探针，检测结直肠癌中PD-L1的表达变化。结合肿瘤组织18F-FDG的SUV值、免疫浸润程度、淋巴细胞分布、细胞因子水平以及免疫相关基因突变频率和表达水平，研究PD-L1分子影像学指标与免疫治疗反应的相关性。基于朴素贝叶斯算法构建综合的预后和治疗反应的预测模型，并提供基于分子影像学特征筛选结直肠癌PD-L1免疫治疗相关生物学标志物的医学影像辅助诊断平台，有利于患者免疫治疗的选择和临床医生精准制定治疗策略。

以抗体为探针的分子影像学检查是结直肠癌无创动态检测的新方法。免疫检测点PD-1/PD-L1是结直肠癌肿瘤耐受的重要机制。在肿瘤组织中精准监测PD-L1有助于免疫治疗选择、疗效及预后评估。结合肿瘤组织影像学特征参数、免疫浸润程度、淋巴细胞分布、细胞因子水平以及免疫相关基因突变频率和表达水平，研究PD-L1分子影像学指标与免疫治疗反应的相关性。基于朴素贝叶斯算法构建综合的诊断和预后预测模型，有利于患者免疫治疗的选择和临床医生精准制定治疗策略。.本项目基本完成了项目研究计划及预期研究成果：①成功制备了基于 PD-L1 抗体的放射性（89Zr-Df-PD-L1 mAb、131I-PD-L1 mAb）和光学（NIR-PD-L1 mAb）分子探针，分析了分子探针的有关特性与体外稳定性，在体外结直肠癌细胞中检测探针与细胞的亲和力，在结直肠癌动物模型中进行了体内分布研究与分子影像学的检测研究，检测结直肠癌中PD-L1的表达变化，建立了多模态的无创性分子影像学动态监测技术；②完成了结直肠癌患者18F-FDG成像特征参数对于PD-L1的无创性诊断价值；并成功研究了结直肠癌18F-FDG的多种代谢参数与肿瘤 TNM 分期以及 GLUT-1 和 MACC1 肿瘤转移相关蛋白的关系；③成功应用并确定了前体素不相干运动扩散加权成像（IVIM）对于晚期直肠癌的诊断性能；④成功证实了基于放射组学列线图模型有助于识别局部晚期直肠癌患者，为预测直肠癌术前T分期及后期治疗决策提供支持；⑤成功证实了基于影像组学模型对直肠癌壁外静脉侵犯（EMVI）的诊断价值，可为临床实践提供决策支持。