聚氨基酸纳米凝胶捕获肿瘤抗原结合免疫调节剂协同增强肿瘤免疫治疗

In comparison with traditional surgical treatment, chemotherapy, and radiotherapy, immunotherapy of tumor has aroused wide attention due to its excellent therapeutic efficacy, lower toxic side effects, and effective inhibition of recurrence, which is considered to be one of the most promising tumor treatment strategies. However, the commonly-used tumor antigens have weak immunogenicity, poor stability, and obvious off-target effects, which dramatically interfere with the efficiency of immune response and the efficacy of tumor inhibition. In this project, we intend to induce the immunogenic cell death of tumor cells in two different ways to obtain apoptotic and necroptotic tumor antigens. Polypeptide nanogel captures tumor antigens and migrates to the draining lymph node along with dendritic cell (DC) agonist R837, which is uptaken by DCs. Subsequently, DCs present antigen and induce tumor-specific T cells to synergistically improve the efficacy of tumor immunotherapy combined with the administration of immune checkpoint inhibitor. Subsequently, we will systemically analyze the two kinds of antigens and compare the similarities and differences of their antigen epitopes to screen the tumor-specific neoantigens and optimize the tumor immunotherapy. The implementation of this project will provide experimental and theoretical bases for the tumor-specific and individual-specific precise tumor immunotherapy in the clinic.

与传统的手术治疗、化学治疗和放射治疗相比，肿瘤免疫治疗因其优异的治疗效果、较低的毒副作用以及有效抑制复发的特性而受到广泛关注，被认为是最具潜力的肿瘤治疗策略之一。但是，常用的肿瘤抗原免疫原性低、稳定性差、脱靶效应明显、机体的免疫应答效率不足且肿瘤治疗效果不理想。本项目拟通过两种不同方式诱导肿瘤细胞发生免疫原性死亡，分别获得凋亡和坏死性凋亡肿瘤抗原。聚氨基酸纳米凝胶捕获肿瘤抗原连同树突状（DC）细胞激动剂R837迁移至引流淋巴结并被DC细胞摄取，提呈抗原并产生肿瘤特异性T细胞，同时结合免疫检查点抑制剂治疗，协同提高肿瘤免疫治疗效果。同时本项目将系统分析两类抗原，比对抗原表位的异同，筛选出肿瘤特异性新抗原，优化肿瘤免疫治疗。本项目的实施将为临床肿瘤特异性和个体特异性精准肿瘤免疫治疗提供实验基础和理论依据。

针对现有肿瘤抗原免疫应答效率不足且肿瘤免疫治疗效果差等问题，本项目提出了“免疫效应生物材料”的概念，设计并可控合成了具有不同手性的聚氨基酸温度敏感凝胶，可以在体内诱导可控的炎症反应，具有作为高效肿瘤免疫治疗佐剂的巨大潜力；设计制备了不同尺寸的多抗原纳米制剂，其中小粒径纳米粒子更容易通过淋巴管在淋巴结中聚集，可以更有效地抑制肿瘤的生长和转移；设计并制备了还原响应性的聚氨基酸纳米凝胶、聚氨基酸宏观/纳米复合凝胶和钙离子（Ca2+）纳米调节器，分别用于负载和靶向递送化疗药阿霉素（DOX）、分子靶向药瑞戈非尼（REG）、转化生长因子-β（TGF-β）抑制剂（LY3200882，LY）和内质网Ca2+释放促进剂姜黄素（CUR），通过化疗、分子靶向治疗、超声等不同的途径或技术诱导或增强肿瘤细胞发生免疫原性死亡，捕获肿瘤抗原并迁移至引流淋巴结，促进树突状细胞（DCs）成熟与活化，诱导产生肿瘤抗原特异性T细胞，协同增强化疗免疫治疗、分子靶向免疫治疗和超声离子调控免疫治疗的肿瘤治疗效果。本项目已完成了预定的研究目标，为临床肿瘤特异性和个体特异性精准免疫治疗提供了实验基础和理论依据。在本项目的资助下，本项目组研究人员在国内外学术期刊上发表学术论文36篇，申请中国发明专利6项，其中授权3项；参加国内和国际会议12次；合作培养博士研究生7名，其中已毕业4名。