MR/PA双模态成像指导下肿瘤血管重构重编程免疫微环境的研究

免疫治疗是一种新兴的肿瘤治疗方法，但是肿瘤内的免疫抑制微环境使肿瘤易发生免疫逃逸以及肿瘤内部药物有效灌注不足降低了治疗效果。有研究表明使肿瘤内异常的血管正常化，有助于氧和药物输送；放射治疗有助于肿瘤抗原暴露。本项目在此基础上，拟采用乳腺癌动物模型通过不同分割方式放射治疗诱导肿瘤血管重构，使其趋于正常化并对肿瘤内免疫微环境进行重编程，使其利于免疫细胞向肿瘤内浸润，同时清除免疫抑制细胞、增强肿瘤免疫原性，充分发挥效应细胞的免疫杀伤效能。本项目拟用MR/PA双模态成像使用纳米尺度的对比剂来实时监测并定量分析肿瘤血管的形态和功能以及肿瘤微环境的变化，探讨血管重构过程中MR/PA双模态成像的最佳模式，提高对血管正常化的判断价值。此外通过免疫荧光、分子生物学、流式细胞等技术研究放射治疗诱导的肿瘤血管正常化重编程免疫抑制微环境的作用机制，探讨放射治疗联合免疫治疗的最佳方案，为提高免疫治疗疗效提供新思路。

Immunotherapy is a new treatment method for malignant tumors. However, due to the immunosuppressive microenvironment in tumors prone to immune escape and insufficient perfusion of drugs in tumor reduced the effect of immunotherapy. Some studies have shown that normalizing abnormal tumor vessels is conducive to the delivery of oxygen and drugs. In addition, radiotherapy is helpful for tumor antigen exposure. Based on the study of vascular normalization, this project intends to use breast cancer animal models to induce tumor vascular remodeling through different segmentation methods of radiation therapy, promote to normalize, and reprogram the immune microenvironment in the tumor to make it beneficial to immune cells. It will remove the immunosuppressive state and make it conducive to the infiltration of immune cells to the tumor while removing immunosuppressive immune cells and enhancing tumor immunogenicity so as to improve the effector cells immune killing effect. This project intends to use MR / PA dual-modality imaging with nano-scale contrast agents to monitor and quantitatively analyze the morphology and function of tumor vessels and the changes of tumor microenvironment in real time. Furthermore, we will explore the model of MR / PA dual-modality imaging during vascular remodeling and improve the judgment value of vascular normalization. In addition, immunofluorescence, molecular biology and flow cytometry will be used in this project to study the role of radiation therapy-induced vascular normalization to reprogram the immunosuppressive microenvironment. It will also explore the best scheme of radiation therapy combined with immunotherapy to improve immunotherapy.