“细胞膜改造促DC/肿瘤细胞融合”疫苗设计新策略及抗肿瘤效应

Despite of rapidly growing progress, immunotherapy has yet benefitted only limited population of patients for the absence of cytotoxicity T cell. As a highly effective vaccine strategy for the activation of cytotoxicity T cell, DC/tumor fusion cell vaccines (DC/tumor FCVs) is expected to expand the subset of people who will benefit from immunotherapy. However, the traditional “passive fusion” strategy suffers from the low fusion efficiency and poor immunogenicity of FCVs, which have impeded the clinic success of FCVs. In this project, we proposed an "active fusion" strategy for FCVs based on the sulfhydryl chemistry of cell surface. First, protein nanoparticles containing activated thiol groups are designed to engineer tumor surface and thus activated thiol groups is introduced to tumor surface. Second, the fast and efficient reactions between activated thiol groups on tumor surface and sulfhydryl groups on DC facilitates the "active” adhesion and fusion of tumor and DC, thus improving the fusion efficiency greatly. The surface engineering of tumor cells as well as the enhanced fusion efficiency have preliminarily been verified. In addition, the immune adjuvant CpG is designed to pre-packed into the protein nanoparticles to further enhance the immunogenicity and anti-tumor immune effect of FCVs. This project aims to not only provide new strategy for the FCVs, but also to pave the new route for vaccine development with the clinic impact.

尽管免疫治疗风起云涌，频频带来惊喜，但仍仅惠及少数患者，因为体内存在杀伤性T细胞是有效前提。作为一种高效激活杀伤性T细胞的疫苗技术，DC/肿瘤融合细胞疫苗被寄予厚望，以扩大免疫治疗受益人群占比。然而，传统“被动”融合技术融合效率普遍不高，致使所得融合疫苗的免疫原性不理想，难以充分发挥融合疫苗优势。针对以上瓶颈，本项目基于细胞表面巯基化学，发展一种全新的“主动融合”策略。其核心是利用巯基活化蛋白纳米颗粒（改造剂）对肿瘤细胞膜表面进行改造，得到表面富含活化巯基的肿瘤细胞。进而仿病毒感染过程中二硫键促融合，利用肿瘤表面活化巯基与DC表面巯基的快速、高效反应形成二硫键，实现肿瘤细胞与DC间的主动粘附与融合，以提高融合效率。其可行性已得到初步验证。此外，拟通过在改造剂中引入免疫佐剂CpG，进一步增强融合疫苗的免疫原性，提高抗肿瘤免疫效应。本项目的实施，将为疫苗设计提供新思路、新方法，推动领域发展。

DC/肿瘤融合疫苗具有重要的 T 细胞激活扩增功能。然而，传统“被动”融合技术融合效率普遍不高，致使所得融合疫苗的免疫原性不理想，难以充分发挥融合疫苗优势。针对以上瓶颈，本项目基于细胞表面巯基化学，发展了一种全新的“主动融合”策略。该策略利用巯基活化蛋白纳米颗粒对肿瘤细胞膜表面进行改造，得到表面富含活化巯基的肿瘤细胞。进而利用肿瘤表面活化巯基与DC表面巯基的快速、高效反应形成二硫键，实现肿瘤细胞与DC间的主动粘附与融合，极大地提高了融合效率。且改造后，在保持肿瘤细胞活性的同时，抑制其增值能力。故所得疫苗提高了肿瘤组织内 CD8+ T 细胞的含量，产生了良好的抗肿瘤免疫效应。本项目的实施，为细胞疫苗的设计提供了全新思路，更将促进人工材料与活细胞的相互融合与协同发展。