Tian Hongjian, Zeng Wenfeng, Wang Zihao, Li Siqi, Wei Wenjing, Li Shanshan, Yin Xiaozhe, Na Wenjing, Wang Youwang, Song Kai, Zhu Ping, Liang Wei
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Biomaterials. 2025 Oct;321:123333. doi: 10.1016/j.biomaterials.2025.123333. Epub 2025 Apr 10.
The clinical benefits of personalized therapeutic tumor vaccines are mainly challenged by the need to identify immunogenic neoantigens promptly, given the rapid pace of tumor mutations. An increasing body of literature addresses the potential of tumor-derived extracellular vesicles (TEVs) as an anti-tumor "cell-free" vaccine due to their substantial presence of neoantigens. However, their immunosuppression and limited presentation efficiency of dendritic cells (DCs) restrict their further application. Here, we have developed a novel tumor-personalized vaccine, termed P-Pev, based on remodeled TEVs by polymeric surfactant polyethylene glycol-phosphatidyleolamine (PEG-PE) and adjuvant monophosphoryl lipid A (MPLA). Our results show that PEG-PE transforms TEVs into micelle-like complexes by disrupting the original structure, facilitating antigens delivery to the cytoplasm, and cross-presentation by DCs. P-Pev particularly prevents the immunosuppressive impacts of TEVs on the ability of DCs to prime CD8 T cells and eliminates the potency of TEVs to promote lung metastasis through their membrane-bound PD-L1. Finally, the P-Pev effectively induces neoantigen-specific cytotoxic T lymphocytes (CTLs) responses and exhibits excellent therapeutic effects in various murine tumor models. Also, the P-Pev induces neoantigen-specific antibodies, suggesting the involvement of humoral immunity in its anti-tumor effects. More importantly, it has been shown that P-Pev prepared by mutated tumor cells can retard these mutated tumor cell-established syngeneic tumors better than P-Pev prepared by original tumor cells, indicating the feasibility that leverages TEVs to prepare personalized tumor vaccines, and it is synergistically enhanced by PD-1 mAb combination. Collectively, we present a general strategy that offers a streamlined, cost-effective, and time-consuming approach to preparing personalized therapeutic tumor vaccines.
鉴于肿瘤突变速度很快，及时识别免疫原性新抗原的需求对个性化治疗性肿瘤疫苗的临床益处构成了主要挑战。越来越多的文献探讨了肿瘤衍生的细胞外囊泡（TEV）作为一种抗肿瘤“无细胞”疫苗的潜力，因为它们大量存在新抗原。然而，它们的免疫抑制作用以及树突状细胞（DC）的呈递效率有限，限制了它们的进一步应用。在此，我们基于用聚合物表面活性剂聚乙二醇 - 磷脂酰乙醇胺（PEG - PE）和佐剂单磷酰脂质A（MPLA）重塑的TEV，开发了一种新型的肿瘤个性化疫苗，称为P - Pev。我们的结果表明，PEG - PE通过破坏原始结构将TEV转化为胶束样复合物，促进抗原递送至细胞质，并由DC进行交叉呈递。P - Pev特别能防止TEV对DC启动CD8 T细胞能力的免疫抑制影响，并消除TEV通过其膜结合的PD - L1促进肺转移的能力。最后，P - Pev有效地诱导新抗原特异性细胞毒性T淋巴细胞（CTL）反应，并在各种小鼠肿瘤模型中表现出优异的治疗效果。此外。P - Pev诱导新抗原特异性抗体，表明体液免疫参与其抗肿瘤作用。更重要的是，已表明由突变肿瘤细胞制备的P - Pev比由原始肿瘤细胞制备的P - Pev能更好地抑制这些突变肿瘤细胞建立的同基因肿瘤，这表明利用TEV制备个性化肿瘤疫苗的可行性，并且它通过与PD - 1单克隆抗体联合使用而得到协同增强。总体而言，我们提出了一种通用策略，为制备个性化治疗性肿瘤疫苗提供了一种简化、经济高效且耗时的方法。
