Enhanced Class I Tumor Antigen Presentation via Cytosolic Delivery of Exosomal Cargos by Tumor-Cell-Derived Exosomes Displaying a pH-Sensitive Fusogenic Peptide,Molecular Pharmaceutics

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Enhanced Class I Tumor Antigen Presentation via Cytosolic Delivery of Exosomal Cargos by Tumor-Cell-Derived Exosomes Displaying a pH-Sensitive Fusogenic Peptide
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-10-13 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00760
Masaki Morishita ₁ , Yuki Takahashi ₁ , Makiya Nishikawa ₁ , Reiichi Ariizumi ₁ , Yoshinobu Takakura ₁

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Tumor-cell-derived exosomes contain endogenous tumor antigens and can be used as a potential cancer vaccine without requiring identification of the tumor-specific antigen. To elicit an effective antitumor effect, efficient tumor antigen presentation by MHC class I molecules on dendritic cells (DC) is desirable. Because DC endocytose exosomes, an endosomal escape mechanism is required for efficient MHC class I presentation of exosomal tumor antigens. In the present study, efficient cytosolic delivery of exosomal tumor antigens was performed using genetically engineered tumor-cell-derived exosomes and pH-sensitive fusogenic GALA peptide. Murine melanoma B16BL6 cells were transfected with a plasmid vector encoding a streptavidin (SAV; a protein that binds to biotin with high affinity)–lactadherin (LA; an exosome-tropic protein) fusion protein to obtain SAV–LA-modified exosomes (SAV-exo). SAV-exo was mixed with biotinylated GALA to obtain GALA-modified exosomes (GALA-exo). Fluorescent microscopic observation using fluorescent-labeled GALA showed that the exosomes were modified with GALA. GALA-exo exerted a membrane-lytic activity under acidic conditions and efficiently delivered exosomal cargos to the cytosol. Moreover, DC treated with GALA-exo showed enhanced tumor antigen presentation capacity by MHC class I molecules. Thus, genetically engineered GALA-exo are effective in controlling the intracellular traffic of tumor-cell-derived exosomes and for enhancing tumor antigen presentation capacity.

中文翻译：

通过显示pH敏感融合肽的肿瘤细胞衍生外泌体通过胞质运送外泌体货物增强I类肿瘤抗原的呈现。

肿瘤细胞衍生的外泌体含有内源性肿瘤抗原，无需鉴定肿瘤特异性抗原即可用作潜在的癌症疫苗。为了引起有效的抗肿瘤作用，由MHC I类分子在树突细胞（DC）上有效地呈递肿瘤抗原是理想的。由于DC胞吞内吞体，有效的MHC I类外泌体肿瘤抗原呈递需要内体逃逸机制。在本研究中，使用基因工程改造的肿瘤细胞衍生的外来体和pH敏感的融合GALA肽有效地进行了外泌体肿瘤抗原的胞质递送。用编码链霉亲和素（SAV；一种以高亲和力与生物素结合的蛋白质）-乳黏着蛋白（LA；一种外泌体蛋白）融合蛋白以获得SAV–LA修饰的外泌体（SAV-exo）。将SAV-exo与生物素化的GALA混合以获得GALA修饰的外泌体（GALA-exo）。使用荧光标记的GALA的荧光显微镜观察表明，外泌体被GALA修饰。GALA-exo在酸性条件下发挥了膜溶解活性，并有效地将外泌体货物运送到细胞质中。此外，用GALA-exo处理的DC通过I类MHC分子显示出增强的肿瘤抗原呈递能力。因此，基因工程GALA-exo在控制肿瘤细胞来源的外来体的细胞内运输和增强肿瘤抗原呈递能力方面是有效的。使用荧光标记的GALA的荧光显微镜观察表明，外泌体被GALA修饰。GALA-exo在酸性条件下发挥了膜溶解活性，并有效地将外泌体货物运送到细胞质中。此外，用GALA-exo处理的DC通过I类MHC分子显示出增强的肿瘤抗原呈递能力。因此，基因工程GALA-exo在控制肿瘤细胞来源的外来体的细胞内运输和增强肿瘤抗原呈递能力方面是有效的。使用荧光标记的GALA的荧光显微镜观察表明，外泌体被GALA修饰。GALA-exo在酸性条件下发挥了膜溶解活性，并有效地将外泌体货物运送到细胞质中。此外，用GALA-exo处理的DC通过I类MHC分子显示出增强的肿瘤抗原呈递能力。因此，基因工程GALA-exo在控制肿瘤细胞来源的外来体的细胞内运输和增强肿瘤抗原呈递能力方面是有效的。

更新日期：2017-10-13

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