Engineering irradiated tumor-derivedmicroparticles as personalized vaccines toenhance antitumor immunity

The inadequate activation of antigen-presenting cells, the entanglement of T cells, and the highly immunosuppressive conditions in the tumor microenvironment (TME) are important factors that limit the effect of cancer vaccines. Studies have shown that individualized and broad antigens can fully activate anti-tumor immunity and inhibiting the function of TGF-ß can facilitate T cell migration to tumor sites. Based on our previous study, we introduced a new vaccine strategy by engineering irradiated tumor cell-derived microparticles (RT-MPs), which have both individualized and broad antigens, to induce broad antitumor effects and cause immunogenic death. Encouraged by the proinflammatory effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the high affinity between TGF-ßR2 and TGF-ß, we developed RT-MPs with the SARS-CoV-2 spike protein and TGF-ßR2. We found that this spike protein and high TGF-ßR2 expression induces the innate immune response and ameliorates the immunosuppressive TME, thereby promoting T cell activation and infiltration, and ultimately inhibiting tumor growth. In addition, when combined with anti-programmed death 1 (anti-PD-1) the engineered RT-MPs were able to generate an immune memory response and eliminate subcutaneous tumors. Our study provides a novel strategy for producing an effective personalized anti-tumor vaccine for clinical application. Overall design: Comparative gene expression profiling analysis of RNA-seq data for Bone marrow derived dentritic cells and RT-MP treated Bone marrow derived dentritic cells.

抗原呈递细胞激活不足、T细胞功能紊乱以及肿瘤微环境（tumor microenvironment, TME）内高度的免疫抑制状态，是限制肿瘤疫苗疗效的重要因素。研究表明，个性化广谱抗原可充分激活抗肿瘤免疫，而抑制转化生长因子β（TGF-β）的功能可促进T细胞向肿瘤部位迁移。基于前期研究，我们提出了一种新型疫苗策略：通过工程化改造辐照肿瘤细胞来源微粒（irradiated tumor cell-derived microparticles, RT-MPs）——这类微粒兼具个性化与广谱抗原特性——以诱导广泛的抗肿瘤效应并引发免疫原性死亡。受新型冠状病毒（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）刺突蛋白的促炎作用以及转化生长因子β受体II（TGF-βR2）与TGF-β的高亲和力特性启发，我们开发了搭载SARS-CoV-2刺突蛋白与TGF-βR2的RT-MPs。研究发现，该刺突蛋白与高表达的TGF-βR2可诱导固有免疫应答，改善免疫抑制性肿瘤微环境，进而促进T细胞活化与浸润，最终抑制肿瘤生长。此外，当与抗程序性死亡蛋白1（anti-PD-1）联合使用时，工程化改造的RT-MPs可诱导免疫记忆应答，清除皮下肿瘤。本研究为开发可用于临床的高效个性化抗肿瘤疫苗提供了全新策略。整体实验设计：对骨髓来源树突状细胞与经RT-MPs处理的骨髓来源树突状细胞的RNA测序（RNA-seq）数据进行比较基因表达谱分析。