Thone Melissa N, Chung Jee Young, Ingato Dominique, Lugin Margaret L, Kwon Young Jik
Department of Chemical and Biomolecular Engineering, University of California, Irvine, CA 92697, United States.
Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States.
Adv Ther (Weinh). 2023 Jan;6(1). doi: 10.1002/adtp.202200125. Epub 2022 Sep 13.
Dendritic cells (DCs) are prime targets for vaccination and immunotherapy. However, limited control over antigen presentation at a desired maturation status in these plastic materials remains a fundamental challenge in efficiently orchestrating a controlled immune response. DC-derived extracellular vesicles (EVs) can overcome some of these issues, but have significant production challenges. Herein, we employ a unique chemically-induced method for production of DC-derived extracellular blebs (DC-EBs) that overcome the barriers of DC and DC-derived EV vaccines. DC-EBs are molecular snapshots of DCs in time, cell-like particles with fixed stimulatory profiles for controlled immune signalling. DC-EBs were produced an order of magnitude more quickly and efficiently than conventional EVs and displayed stable structural integrity and antigen presentation compared to live DCs. Multi-omic analysis confirmed DC-EBs are majorly pure plasma membrane vesicles that are homogeneous at the single-vesicle level, critical for safe and effective vaccination. Immature vs. mature molecular profiles on DC-EBs exhibited molecularly modulated immune responses compared to live DCs, improving remission and survival of tumor-challenged mice via generation of antigen-specific T cells. For the first time, DC-EBs make their case for use in vaccines and for their potential in modulating other immune responses, potentially in combination with other immunotherapeutics.
树突状细胞（DCs）是疫苗接种和免疫治疗的主要靶点。然而，在这些可塑性细胞中，要将抗原呈递控制在所需的成熟状态仍然存在很大限制，这是有效协调可控免疫反应的一项根本性挑战。DC来源的细胞外囊泡（EVs）可以克服其中一些问题，但在生产方面存在重大挑战。在此，我们采用一种独特的化学诱导方法来生产DC来源的细胞外小泡（DC-EBs），该方法克服了DC和DC来源的EV疫苗的障碍。DC-EBs是DC在特定时间的分子快照，是具有固定刺激特征的类细胞颗粒，用于可控的免疫信号传导。与传统的EVs相比，DC-EBs的生产速度更快、效率更高，快了一个数量级，并且与活的DCs相比，其结构完整性和抗原呈递表现稳定。多组学分析证实，DC-EBs主要是纯的质膜囊泡，在单囊泡水平上是均匀的，这对于安全有效的疫苗接种至关重要。与活的DCs相比，DC-EBs上未成熟与成熟的分子特征表现出分子调节的免疫反应，通过产生抗原特异性T细胞提高了荷瘤小鼠的缓解率和生存率。DC-EBs首次证明了其在疫苗中的应用价值及其在调节其他免疫反应方面的潜力，可能与其他免疫治疗方法联合使用。
