肿瘤细胞和T淋巴细胞双重靶向的功能化外泌体激活前列腺癌特异性免疫研究

CD8 + T cell-mediated immune response plays a major role in the tumor immune clearance. Programmed death receptor 1 (PD-1) which is widely distributed on the surface of T cells binds its ligand (PD-L1) on the surface of tumor cells, causing the immunosuppression of T cells. T cells gathering in tumor tissue without costimulatory molecules can also result in T cell immune inactivation. The two ways both play important role in the tumor immune escape. In this study, functional exosomes are connected with anti-PD-L1 monoclonal antibody and anti-CD28 antibody through PEG in order to construct a drug delivery system dual-targeting tumor cells and T cells for immunotherapy.The system can mediated the binding of T cells and tumor cells that simultaneously block the inhibitory checkpoint PD-1/PD-L1 signal and stimulate T cells via the CD28 co-stimulatory pathway.The research is expected to combine the exosome-based nano-delivery technology and the tumor immunotherapy technology to treat advanced prostate cancer. The two different mechanisms can activate the body's tumor-specific immunity by blocking tumor immune escape and activation of T cells for the purpose of using the body's own immune system to clear prostate cancer cells. The study will open up a new way for the treatment of advanced prostate cancer and provide ideas for the construction of immunotherapy drug delivery systems for other tumors.

CD8+T细胞介导的免疫应答在肿瘤的免疫清除中起主要作用。T细胞表面的程序化死亡受体1(PD-1)与肿瘤细胞表面的配体PD-L1结合，可引起T细胞的免疫抑制。另外肿瘤组织富集的T细胞缺乏共刺激信号分子的活化，也可导致T细胞免疫失活，两者均是肿瘤免疫逃逸重要原因。本课题将PD-L1单抗和CD28抗体与功能化外泌体通过PEG桥接，构建双重靶向肿瘤细胞和T细胞的免疫治疗给药系统，介导肿瘤细胞与T细胞结合，阻断免疫检查点PD-1/PD-L1途径，并激活CD28共刺激通路，两者协同发挥作用。通过课题研究有望能够在晚期前列腺癌的治疗中，将基于外泌体的纳米输送技术与肿瘤免疫治疗技术结合应用，利用阻断肿瘤免疫逃逸和活化T细胞两个不同机制，激活机体的肿瘤特异性免疫，达到利用机体自身免疫系统清除前列腺癌细胞的目的。从而为晚期前列腺癌的治疗开辟新途径，也为肿瘤的免疫治疗给药系统构建提供思路。

本课题针对肿瘤和浸润淋巴细胞高表达PD-1/PD-L1以及共刺激信号缺乏导致抗肿瘤免疫无法有效激活的背景，构建双重靶向肿瘤细胞和细胞毒性T细胞的纳米免疫治疗给药系统。我们从阻断肿瘤免疫逃逸和活化T细胞两个不同机制，激活肿瘤特异性免疫，达到利用机体自身免疫系统清除肿瘤的目的，为晚期肿瘤的免疫治疗提供理论依据和新思路。本研究探索并构建表征了适宜的小分子药物/抗体药物共递送载体SHRP，以其为基础建立了共载芳烃受体（AhR）抑制剂CH223191及anti-CD28的免疫胶束体系Dual-SHRP。我们在前期进行多肿瘤细胞系探索时，发现此药物递送系统在乳腺癌模型中的抗肿瘤效果优于在前列腺癌模型中的作用。查阅文献发现，两种肿瘤模型的淋巴浸润情况差异较大，乳腺癌相较于前列腺癌具备更多的淋巴浸润，对免疫治疗的响应更优，因此后续的研究重点在乳腺癌模型中进行探索。首先在体外细胞水平探究递送体系的免疫调控作用及抗乳腺癌效果；随后在体内小鼠乳腺癌模型中验证其抗肿瘤效果及安全性等。上述研究共同阐明了AhR受体调节药物联合共刺激信号药物调控肿瘤微环境的潜力，为肿瘤免疫治疗提供了一种新的思路。本项目资助下在Mater Today Bio、J Control Release、Mol Pharm、Int J Nanomedicine、ACS Appl Mater Interfaces等期刊发表相关SCI论文9篇，发表中文核心期刊论文2篇。