肿瘤微环境多指标分子影像方法及其在免疫治疗预后中的应用探索

Cancer immunotherapy has attracted tremendous interests in recent years. Breast cancer is a very common type of cancers for women. While it is known that the tumor microenvironment (TME) plays a critical role in the resistance of tumors to different types of therapies, the relationship between the response rates of breast cancer patients to immune check-point blockade (ICB) therapy and the TME features still needs further in-depth investigations. Therefore, to realize highly effective breast cancer immunotherapy, it would be of great significance to develop innovative molecular imaging probes to monitor the complicated TME. In this project, based on our previous experience on the fabrication of TME-responsive imaging probes, TME modulation techniques, as well as cancer immunotherapy, we would like to develop innovative photoacoustic imaging probes for detection of tumor hypoxia, acidity and many other physiological indexes, and SPECT imaging probes for the evaluation immune-suppressive TME inside breast tumors. By utilizing these molecular imaging probes, we would carefully study the correlation effects between the unique TME physiological features (e.g. oxygen level, pH, ROS) to the immune-suppressive microenvironment within breast cancer tumors. Afterwards, we would explore the influence of such complicated TME on the treatment outcomes of ICB treatments (e.g. anti-PD-1, anti-PD-L1, anti-CTLA-4), as well as how to increase the therapeutic efficacy of such ICB treatments via the TME modulation. By completing the project in this proposal, we would try to fabricate novel molecular imaging probes for noninvasive visualization of the dynamic changes of TME, so as to elucidate the correlation between the dynamic changes of breast cancer TME and the prognosis of cancer ICB treatment. Moreover, this project would provide valuable experimental and theoretical information for potential clinical studies in the personalized immunotherapy of breast cancer.

免疫治疗是当前备受关注的一类新型肿瘤治疗策略。乳腺癌作为女性高发肿瘤之一，其对免疫检查点阻断疗法的响应与其肿瘤微环境之间的关联有待深入探讨。因此，发展乳腺癌微环境多指标分子影像技术，有望为安全高效的免疫治疗策略的选择提供具有指导意义的影像学信息。在本项目中，申请人拟在项目团队前期分子影像探针研究、肿瘤微环境调控、肿瘤免疫治疗等方面的工作基础之上，发展针对肿瘤乏氧、微酸等生理指标的光声探针和针对肿瘤免疫微环境的SPECT探针，并据此研究乳腺癌微环境生理指标与免疫微环境之间的关联机制，进而全面系统地阐释乳腺癌微环境与免疫检查点阻断疗法疗效之间的相互关系。力争通过本项目的开展，构建针对乳腺癌微环境动态变化过程多指标监测的分子影像探针，阐明乳腺癌微环境的动态变化过程与免疫治疗预后之间的相互关系，为指导未来乳腺癌临床免疫治疗的分级分型、实现个性化免疫治疗提供理论支撑和具有临床转化价值的影像技术。

该项目按照原计划发展针对肿瘤乏氧、微酸等生理指标的光声探针和针对肿瘤免疫微环境的SPECT探针，并据此研究乳腺癌微环境生理指标与免疫微环境之间的关联机制，进而全面系统地阐释乳腺癌微环境与免疫检查点阻断疗法疗效之间的相互关系；同时构建针对乳腺癌微环境动态变化过程多指标监测的分子影像探针，阐明乳腺癌微环境的动态变化过程与免疫治疗预后之间的相互关系，有望为指导未来乳腺癌临床免疫治疗的分级分型、实现个性化免疫治疗提供理论支撑和具有临床转化价值的影像技术。项目执行期间，在 Nature Communications、Proc Natl Acad Sci USA、Matter、 Chemical Society Review 、Advanced Materials、Advanced Functional Materials、Nano Letter、Biomaterials等高水平学术期刊发表第一/通讯作者论文 17篇；申请国家发明专利 9件，授权 1件；申请获批了科技部重点研发计划青年项目一项；入选美国科睿唯安公布的“全球高被引科学家名单”（Highly Cited Researchers）（交叉学科）（2019、2021、2022）、江苏省“六大人才高峰”高层次人才（2020）、 Biomaterials Science Emerging Investigators （2020）、江苏省双创人才（2021）、MIT Technology Review Innovators Under 35（2021）、教育部青年长江学者（2021）等。