Ocean College , Zhejiang University , Zhoushan 316021 , China.
ACS Appl Mater Interfaces. 2018 Oct 3;10(39):33532-33544. doi: 10.1021/acsami.8b10081. Epub 2018 Sep 19.
Cellular immunity is essential for the effectiveness of vaccines against cancer. After capture of vaccines, dendritic cells (DCs) have to migrate to lymph nodes via chemokine receptor type 7 (CCR7). Subsequently, DCs present cytosolic antigens via major histocompatibility complex class I (MHC I) molecules to induce cellular immunity. However, various vaccines fail to induce potent cellular immunity due to insufficient MHC I-restricted antigen presentation and limitations of immune adjuvants. Hence, we constructed novel immune adjuvant targeting micelles (M-COSA) to targeted codeliver antigen ovalbumin (OVA) and plasmid DNA encoding CCR7 (CCR7 pDNA) to the cytosol of DCs, thus promoting DC migration to lymph nodes to boost MHC I-restricted antigen presentation. M-COSA exhibited adjuvant activity and demonstrated more efficient DC cellular uptake compared with COSA. M-COSA/OVA/pDNA increased costimulatory molecule expression and cytokine secretion, resulting in DC activation and maturation. Moreover, antigens and pDNA, which were encapsulated in micelles, escaped from the endosome into the cytoplasm to achieve MHC I-restricted antigen presentation and increase CCR7 expression. The number of CD8 T cells, which was positively correlated with tumor rejection, was notably increased and tumor growth was dramatically suppressed after vaccination with M-COSA/OVA/pDNA. In summary, M-COSA/OVA/pDNA micelles, which allow DC targeting and efficient DC migration to lymph nodes to enhance cellular immunity, exhibit effective tumor inhibition and lay the foundation for novel vaccine design.
细胞免疫对于癌症疫苗的有效性至关重要。疫苗被捕获后,树突状细胞(DC)必须通过趋化因子受体 7(CCR7)迁移到淋巴结。随后,DC 通过主要组织相容性复合体 I 类(MHC I)分子呈现细胞溶质抗原,以诱导细胞免疫。然而,由于 MHC I 受限的抗原呈递不足和免疫佐剂的限制,各种疫苗未能诱导有效的细胞免疫。因此,我们构建了新型免疫佐剂靶向胶束(M-COSA),以靶向共递呈抗原卵清蛋白(OVA)和编码 CCR7 的质粒 DNA(CCR7 pDNA)至 DC 的细胞质,从而促进 DC 迁移到淋巴结以增强 MHC I 受限的抗原呈递。M-COSA 表现出佐剂活性,并显示出比 COSA 更高的 DC 细胞摄取效率。M-COSA/OVA/pDNA 增加了共刺激分子的表达和细胞因子的分泌,导致 DC 的激活和成熟。此外,包封在胶束中的抗原和 pDNA 从内体逃逸到细胞质中,以实现 MHC I 受限的抗原呈递并增加 CCR7 的表达。与肿瘤排斥呈正相关的 CD8 T 细胞数量明显增加,用 M-COSA/OVA/pDNA 接种后肿瘤生长受到显著抑制。总之,M-COSA/OVA/pDNA 胶束可靶向 DC 并有效迁移至淋巴结以增强细胞免疫,可有效抑制肿瘤,为新型疫苗设计奠定基础。
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