Abstract：
Radiated tumor cell-derived extracellular vesicles (RT-EVs) encapsulate abundant DNA fragments from irradiated tumor cells, in addition to acting as integrators of multiple tumor antigens. Accumulating evidence indicates these DNA fragments from damaged cells are involved in downstream immune responses, but most of them are degraded in cells before incorporation into derived RT-EVs, thus the low abundance of DNA fragments limits immune responses of RT-EVs. Here, this study found that different radiations affected fates of DNA fragments in RT-EVs. Boron neutron capture therapy (BNCT) induced DNA accumulation in RT-EVs (BEVs) by causing more DNA breaks and DNA oxidation resisting nuclease degradation. This is attributed to the high-linear energy transfer (LET) properties of alpha particles from the neutron capture reaction of 10B. When being internalized by dendritic cells (DCs), BEVs activated the DNA sensing pathway, resulting in functional enhancements including antigen presentation, migration capacity, and cytokine secretion. After vaccination of the BEVs-educated DCs (BEV@BMDCs), the effector T cells significantly expanded and infiltrated into tumors, suggesting robust anti-tumor immune activation. BEV@BMDCs not only effectively inhibited the primary tumor growth and metastasis formation but also elicited long-term immune memory. In conclusion, a successful DC vaccine is provided as a promising candidate for tumor vaccine.
摘要：
辐射肿瘤细胞衍生的细胞外囊泡（RT-EV）封装了来自辐射肿瘤细胞的丰富DNA片段，除了充当多种肿瘤抗原的整合者。越来越多的证据表明，这些来自受损细胞的DNA片段参与了下游免疫反应，但是它们中的大多数在掺入衍生的RT-EV之前在细胞中降解，因此，低丰度的DNA片段限制了RT-EV的免疫反应。这里,这项研究发现，不同的辐射会影响RT-EV中DNA片段的命运。硼中子捕获疗法（BNCT）通过引起更多的DNA断裂和DNA氧化抵抗核酸酶降解来诱导RT-EV（BEV）中的DNA积累。这归因于10B的中子俘获反应的α粒子的高线性能量转移（LET）特性。当被树突状细胞（DC）内化时，BEV激活了DNA传感通路，导致包括抗原呈递在内的功能增强，迁移能力，和细胞因子分泌。接种BEV教育的DC（BEV@BMDCs）后，效应T细胞显著扩增并浸润到肿瘤中，表明强大的抗肿瘤免疫激活。BEV@BMDCs不仅能有效抑制原发肿瘤的生长和转移形成，还能引起长期免疫记忆。总之,提供了一种成功的DC疫苗作为肿瘤疫苗的有希望的候选物。
