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将 CIITA 基因导入肿瘤细胞可产生具有增强抗肿瘤作用的外泌体。

Introduction of the CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects.

机构信息

Tumor Immunity Medical Research Center, Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.

出版信息

Exp Mol Med. 2011 May 31;43(5):281-90. doi: 10.3858/emm.2011.43.5.029.

Abstract

Exosomes are small membrane vesicles secreted from various types of cells. Tumor-derived exosomes contain MHC class I molecules and tumor-specific antigens, receiving attention as a potential cancer vaccine. For induction of efficient anti-tumor immunity, CD4+ helper T cells are required, which recognize appropriate MHC class II-peptide complexes. In this study, we have established an MHC class II molecule-expressing B16F1 murine melanoma cell line (B16F1- CIITA) by transduction of the CIITA (Class II transactivator) gene. Exosomes from B16-CII cells (CIITA- Exo) contained a high amount of MHC class II as well as a tumor antigen TRP2. When loaded on dendritic cells (DCs), CIITA-Exo induced the increased expression of MHC class II molecules and CD86 than the exosomes from the parental cells (Exo). In vitro assays using co-culture of immunized splenocytes and exosome-loaded DCs demonstrated that CIITA-Exo enhanced the splenocyte proliferation and IL-2 secretion. Consistently, compared to B16-Exo, CIITA-Exo induced the increased mRNA levels of inflammatory cytokines such as TNF-α, chemokine receptor CCR7 and the production of Th1-polarizing cytokine IL-12. A tumor preventive model showed that CIITA-Exo significantly inhibited tumor growth in a dose-dependent manner. Ex vivo assays using immunized mice demonstrated that CIITA-Exo induced a higher amount of Th1-polarized immune responses such as Th1-type IgG2a antibodies and IFN-γ cytokine as well as TRP2-specific CD8+ T cells. A tumor therapeutic model delayed effects of tumor growth by CIITA-Exo. These findings indicate that CIITA-Exo are more efficient as compared to parental Exo to induce anti-tumor immune responses, suggesting a potential role of MHC class II-containing tumor exosomes as an efficient cancer vaccine.

摘要

外泌体是各种细胞分泌的小膜囊泡。肿瘤来源的外泌体包含 MHC Ⅰ类分子和肿瘤特异性抗原,作为潜在的癌症疫苗受到关注。为了诱导有效的抗肿瘤免疫,需要 CD4+辅助 T 细胞,其识别适当的 MHC Ⅱ类-肽复合物。在这项研究中,我们通过转导 CIITA(Ⅱ类转录激活物)基因建立了表达 MHC Ⅱ类分子的 B16F1 小鼠黑色素瘤细胞系(B16F1-CIITA)。B16-CII 细胞(CIITA-Exo)的外泌体含有大量的 MHC Ⅱ类和肿瘤抗原 TRP2。当加载到树突状细胞(DCs)上时,CIITA-Exo 诱导 MHC Ⅱ类分子和 CD86 的表达增加,高于亲本细胞(Exo)的外泌体。体外共培养免疫脾细胞和负载外泌体的 DCs 的实验表明,CIITA-Exo 增强了脾细胞的增殖和 IL-2 的分泌。一致地,与 B16-Exo 相比,CIITA-Exo 诱导 TNF-α、趋化因子受体 CCR7 和 Th1 极化细胞因子 IL-12 的 mRNA 水平增加。肿瘤预防模型表明,CIITA-Exo 以剂量依赖的方式显著抑制肿瘤生长。免疫小鼠的离体实验表明,CIITA-Exo 诱导了更高数量的 Th1 极化免疫反应,如 Th1 型 IgG2a 抗体和 IFN-γ细胞因子以及 TRP2 特异性 CD8+T 细胞。CIITA-Exo 延迟了肿瘤生长的效果。这些发现表明,与亲本 Exo 相比,CIITA-Exo 更有效地诱导抗肿瘤免疫反应,表明含有 MHC Ⅱ类的肿瘤外泌体作为有效癌症疫苗的潜在作用。

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