T细胞受体NRP1作为新型免疫检查点在去势抵抗性前列腺癌中的作用机制研究

晚期去势抵抗性前列腺癌预后差，缺乏有效治疗手段。目前研究显示肿瘤微环境中T细胞免疫功能失调参与前列腺癌进展，而T细胞受体神经纤毛蛋白-1（NRP1）与前列腺癌患者预后相关。我们基于前列腺癌肿瘤组织标本的免疫分析，发现NRP1具有前列腺癌新型免疫检查点的潜能。.本项目拟利用组织微环境多标全景观分析等技术，利用临床样本阐明前列腺癌进展过程中免疫微环境中NRP1阳性T细胞的组成类型、比例、空间定位分布变化特征；利用细胞共培养、信号通路芯片及信号通路阻断实验，解析前列腺癌细胞通过NRP1分子抑制肿瘤杀伤T细胞浸润及功能的作用机制；通过小鼠去势抵抗性前列腺癌模型，验证NRP1可作为前列腺癌免疫治疗的新型免疫检查点的假说。从而解析肿瘤免疫微环境调控前列腺癌进展的新机制，以及NRP1在去势抵抗性前列腺癌免疫治疗中的关键作用；为建立去势抵抗性前列腺癌的免疫治疗新方案提供基础研究证据。

The prognosis of castration-resistant prostate cancer is poor without effective treatment. Recent studies indicate that T cell immune dysfunction in the tumor microenvironment is involved in the progression of prostate cancer. Moreover, T cell receptor NRP1 was reported with association with the prognosis of prostate cancer. Our previous study showed that NRP1 play an essential role in T cell immune function in the progression of prostate cancer. Therefore, it may have the potential to be a novel check point molecule for the immunotherapy of prostate cancer..This project intends to utilize the technology of tissue microenvironment multi-standard full landscape analysis system and other cell biology measures to reveal the temporal and spatial distribution characteristics of NRP1+ T cells and other immune cells in the prostate cancer immune microenvironment in tissue samples from clinical collection. It might elucidate their correlation with the development of advanced prostate cancer. By applying cancer-T cells co-culture system and signaling pathway chip technology, we propose to analyze the NRP1-mediated effect and mechanism between prostate cancer cells and T cells through in vivo and in vitro experiments, which allow us to verify if NRP1 could be used as a novel type of immune checkpoint for prostate cancer immunotherapy. This project will reveal the key role of NRP1 in the immunotherapy of advanced prostate cancer. Our research could provide basic research evidence for the immunotherapy of castration-resistant prostate cancer.