Endolysosomal-Escape Nanovaccines through Adjuvant-Induced Tumor Antigen Assembly for Enhanced Effector CD8+ T Cell Activation
Endolysosomal-Escape Nanovaccines through Adjuvant-Induced Tumor Antigen Assembly for Enhanced Effector CD8+ T Cell Activation
复制标题
通过佐剂诱导的肿瘤抗原组装实现内溶酶体逃逸纳米疫苗以增强效应 CD8 T 细胞激活
DOI：
10.1002/smll.201703539
复制
发表时间：
2018-04-12
期刊：
影响因子：
13.3
通讯作者：
Verdoes, Martijn
中科院分区：
文献类型：
--
作者：
Qiu, Liping;Valente, Michael;Verdoes, Martijn
肿瘤特异性效应免疫细胞的激活是成功免疫治疗的关键，疫苗接种是诱导这种适应性免疫应答的有力策略。然而，产生有效的抗癌疫苗是具有挑战性的。为了克服这些挑战，开发了一种新的直接的策略，即肿瘤诱导的肿瘤抗原组装以产生具有上级抗原/佐剂负载效率的纳米疫苗。为了保护循环中的纳米疫苗并引入额外的功能，安装了生物相容性多酚涂层。所得的可功能化纳米疫苗配备有pH（低）插入肽（pHLIP）以促进内溶酶体逃逸并促进细胞质定位，目的是增强树突状细胞对抗原的交叉呈递以有效地激活CD 8（+）T细胞。结果表明，pHLIP功能化的模型纳米疫苗可以诱导内溶酶体逃逸，并在体外和体内增强CD 8（+）T细胞活化。此外，基于免疫诱导的抗原组装，产生了临床相关的肿瘤相关抗原NY-ESO-1的纳米疫苗，并显示出引发NY-ESO-1特异性CD 8（+）T细胞活化的优异能力，证明了这种可功能化的纳米疫苗制剂策略用于临床应用的高潜力。
The activation of tumor-specific effector immune cells is key for successful immunotherapy and vaccination is a powerful strategy to induce such adaptive immune responses. However, the generation of effective anticancer vaccines is challenging. To overcome these challenges, a novel straight-forward strategy of adjuvant-induced tumor antigen assembly to generate nanovaccines with superior antigen/adjuvant loading efficiency is developed. To protect nanovaccines in circulation and to introduce additional functionalities, a biocompatible polyphenol coating is installed. The resulting functionalizable nanovaccines are equipped with a pH (low) insertion peptide (pHLIP) to facilitate endolysosomal escape and to promote cytoplasmic localization, with the aim to enhance cross-presentation of the antigen by dendritic cells to effectively activate CD8(+) T cell. The results demonstrate that pHLIP-functionalized model nanovaccine can induce endolysosomal escape and enhance CD8(+) T cell activation both in vitro and in vivo. Furthermore, based on the adjuvant-induced antigen assembly, nanovaccines of the clinically relevant tumor-associated antigen NY-ESO-1 are generated and show excellent capacity to elicit NY-ESO-1-specific CD8(+) T cell activation, demonstrating a high potential of this functionalizable nanovaccine formulation strategy for clinical applications.