Antitumor immunity by small extracellular vesicles collected from activated dendritic cells through effective induction of cellular and humoral immune responses
Antitumor immunity by small extracellular vesicles collected from activated dendritic cells through effective induction of cellular and humoral immune responses
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DOI：
10.1016/j.biomaterials.2020.120112
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发表时间：
2020-09-01
期刊：
影响因子：
14
通讯作者：
Takakura, Yoshinobu
中科院分区：
文献类型：
--
作者：
Matsumoto, Akihiro;Asuka, Maho;Takakura, Yoshinobu
树突状细胞衍生的细胞外小囊泡（dc - sev）被认为是一种基于肿瘤抗原的癌症免疫治疗的新候选药物。为了提高dc - sev诱导的抗肿瘤免疫，必须生产能够诱导有效抗原特异性体液和细胞免疫反应的dc - sev。在此，我们从dc中收集sev，并添加卵白蛋白（OVA）作为模型抗原，以及LPS和ifn - γ，以制备具有高免疫活性的dc - sev。在确认收集到的sEV，命名为活化的dcova -sEV，含有OVA并具有免疫相关成分（MHC类分子显示抗原表位和共刺激分子，以及sEV标记蛋白）后，我们发现活化的dcova -sEV通过toll样受体4信号通路刺激巨噬细胞和dc，增强肿瘤微环境中的先天免疫。此外，激活的dcova - sev在体外和体内诱导了有效的抗原特异性体液和细胞免疫反应。最后，用活化的dcova - sev免疫表达ova的肿瘤细胞诱导的荷瘤小鼠，显示出更强的体内抗肿瘤作用。
Dendritic cell-derived small extracellular vesicles (DC-sEVs) are proposed as a novel candidate for tumor antigen-based cancer immunotherapy. In order to improve the DC-sEV-induced antitumor immunity, production of DC-sEVs capable of inducing potent antigen-specific humoral and cellular immune responses is necessary. Here, we collected sEVs from DCs and added ovalbumin (OVA), which was used as model antigen, as well as LPS and IFN-gamma, to prepare DC-sEVs with high immune activity. After confirming that the collected sEVs, named activated-DCOVA-sEVs, contained OVA and possessed immunologically relevant components (MHC class I molecule displaying antigen epitopes and co-stimulatory molecules, as well as sEV marker proteins), we found that activated-DCOVA-sEV stimulated macrophages and DCs through Toll-like receptor 4 signaling and boosted innate immunity in the tumor microenvironment. Moreover, activated-DCOVA-sEVs induced potent antigen-specific humoral and cellular immune responses both in vitro and in vivo. Finally, immunization with activated-DCOVA-sEVs exhibited stronger in vivo antitumor effects in tumor-bearing mice induced by inoculation with OVA-expressing tumor cells.