Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system
Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system
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DOI：
10.1038/s41434-023-00388-z
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发表时间：
2023-03-23
期刊：
影响因子：
5.1
通讯作者：
Yamaue，Hiroki
中科院分区：
文献类型：
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作者：
Tominaga，Shinta;Ojima，Toshiyasu;Yamaue，Hiroki
我们先前报道，转导全长肿瘤相关抗原(TAA)基因的树突状细胞(DC)可诱导TAA特异性细胞毒性T淋巴细胞(CTL)诱导抗肿瘤反应。为了克服DC疫苗治疗所需DC的数量和质量问题，我们重点研究了诱导多能干细胞(IPSCs)作为获取DC的新工具以及IPSCs来源的DC(IPSDCs)的有效性。但在IPSDC疫苗治疗的临床应用中，仍需进一步提高抗肿瘤效果。在这项研究中，我们将中间蛋白(MSLN)作为一种潜在的有用的TAA，并将重点放在泛素-蛋白酶体系统以增强IPSDCs的抗原提呈能力。转导MSLN基因的IPSDCs(IPSDCS-MSLN)诱导的CTL对表达MSLN的自体淋巴母细胞(LCLS-MSLN)具有杀伤活性。转导泛素-MSLN融合基因的IPSDCs诱导的CTL对LCLS-MSLN的杀伤活性高于IPSDCs-MSLN诱导的CTL。本研究旨在通过同时表达泛素和MSLN的转基因IPSDCs的免疫来克服外周T细胞对MSLN的耐受，从而对内源性表达MSLN的肿瘤产生强大的细胞毒作用。因此，该策略作为一种有效的肿瘤疫苗治疗方法在临床应用前景看好。
We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.