口腔鳞癌CD47/SIRPα信号通路调控髓源性抑制细胞表型转换的分子机制研究

本研究聚焦“免疫检查点如何调节肿瘤免疫逃逸”这一重要科学问题，结合前期研究基础，提出“口腔鳞状细胞癌（OSCC）中CD47/SIRPα通过PI3Kγ/c-Rel通路调控髓源性抑制细胞（MDSC）抑制功能参与肿瘤免疫逃逸”的科学假说。利用口腔鳞癌患者标本及免疫健全小鼠模型，拟从以下四个方面开展深入研究：①利用流式及多标记染色技术，探究人和小鼠OSCC中MDSC上SIRPα的表达；②利用细胞分选和共培养技术，探索OSCC中CD47/SIRPα调控MDSC的免疫抑制功能；③利用体内抗体阻断及敲除实验，探究CD47/SIRPα是否特异性依赖MDSC实现免疫抑制功能；④利用Western blot及RT-PCR等方法，探究CD47/SIRPα是否通过调控PI3Kγ/c-Rel调节MDSC功能。本研究旨在揭示CD47/SIRPα调控MDSC的机制，为靶向MDSC提高OSCC治疗响应率提供新的治疗手段。

This research focuses on the important scientific issue of how immune checkpoints regulating tumor immune escape. Based on the previous research, we put forward the scientific hypothesis that CD47/SIRPα regulates the inhibitory function of myeloid-derived suppressor cell (MDSC) through PI3Kγ/c-Rel pathway in the microenvironment of oral squamous cell carcinoma (OSCC) and participates in tumor immune escape. Using OSCC patient specimens and immune-competent OSCC mouse models, we plan to conduct in-depth research from the following four aspects. Firstly, we will evaluate the expression of SIRPα on MDSC by flow cytometry and multi-label staining techniques in human and mouse OSCC. Then, cell sorting and co-culture techniques are used to explore CD47/SIRPα pathway in regulating the immunosuppressive and metabolic functions of MDSC in OSCC. Moreover, we will use the in vivo antibody blocking and knockout experiments to explore whether CD47/SIRPα is specifically dependent on MDSC to achieve immunosuppressive function. Finally, western blot and RT-PCR methods are used to explore whether CD47/SIRPα regulates MDSC function by regulating PI3Kγ/c-Rel pathway. This study aims to reveal the mechanism by which CD47/SIRPα regulates MDSC, and to provide a new treatment method for targeting MDSC to improve the response rate of immunotherapy for oral squamous cell carcinoma.