Combination epidermal growth factor receptor variant III peptide-pulsed dendritic cell vaccine with miR-326 results in enhanced killing on EGFRvIII-positive cells.
Combination epidermal growth factor receptor variant III peptide-pulsed dendritic cell vaccine with miR-326 results in enhanced killing on EGFRvIII-positive cells.
复制标题
表皮生长因子受体变体 III 肽脉冲树突状细胞疫苗与 miR-326 的组合可增强对 EGFRvIII 阳性细胞的杀伤力
DOI：
10.18632/oncotarget.15445
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发表时间：
2017-04-18
期刊：
影响因子：
--
通讯作者：
Jiang C
中科院分区：
文献类型：
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作者：
Li J;Wang F;Wang G;Sun Y;Cai J;Liu X;Zhang J;Lu X;Li Y;Chen M;Chen L;Jiang C
大约三分之一的胶质母细胞瘤 (GBM) 患者中存在表皮生长因子受体 (EGFRvIII) 的 III 型突变体。它在正常组织中从未发现；因此，它代表了 GBM 免疫治疗的候选靶点。 PEPvIII 是来自 EGFRvIII 的肽序列，旨在代表神经胶质瘤的靶标，并由 MHC I/II 复合物呈递。树突状细胞 (DC) 具有使 CD4+ T 和 CD8+ T 细胞敏感以精确靶向和根除 GBM 的巨大潜力。在这里，我们证明PEPvIII可以被DC加载并呈递给T淋巴细胞，特别是PEPvIII特异性CTL，以精确杀死U87-EGFRvIII细胞。除了抑制U87-EGFRvIII细胞增殖和诱导细胞凋亡外，miR-326还降低肿瘤环境中TGF-β1的表达，通过抑制SMO/Gli2轴提高T细胞激活和杀伤功效，至少部分逆转免疫抑制环境。此外，与单独使用任何一种疫苗相比，将 EGFRvIII-DC 疫苗与 miR-326 联合使用能够更有效地杀死 U87-EGFRvIII 细胞。这一发现表明，基于 DC 的疫苗与 miR-326 相结合可能会诱导针对表达相关抗原的 GBM 细胞的更强大的抗肿瘤免疫，这为 GBM 免疫治疗提供了一种有前景的方法。
The mutant Type III variant of epidermal growth factor receptor (EGFRvIII) is present in approximately one-third of glioblastoma (GBM) patients. It is never found in normal tissues; therefore, it represents a candidate target for GBM immunotherapy. PEPvIII, a peptide sequence from EGFRvIII, was designed to represent a target of glioma and is presented by MHC I/II complexes. Dendritic cells (DCs) have great potential to sensitize CD4+ T and CD8+ T cells to precisely target and eradicate GBM. Here, we show that PEPvIII could be loaded by DCs and presented to T lymphocytes, especially PEPvIII-specific CTLs, to precisely kill U87-EGFRvIII cells. In addition to inhibiting proliferation and inducing the apoptosis of U87-EGFRvIII cells, miR-326 also reduced the expression of TGF-β1 in the tumour environment, resulting in improved efficacy of T cell activation and killing via suppressing the SMO/Gli2 axis, which at least partially reversed the immunosuppressive environment. Furthermore, combining the EGFRvIII-DC vaccine with miR-326 was more effective in killing U87-EGFRvIII cells compared with the administration of either one alone. This finding suggested that a DC-based vaccine combined with miR-326 may induce more powerful anti-tumour immunity against GBM cells that express a relevant antigen, which provides a promising approach for GBM immunotherapy.