Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
Gene Ther. 2023 Aug;30(7-8):552-559. doi: 10.1038/s41434-023-00388-z. Epub 2023 Mar 23.
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.
我们之前报道过，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），从而引发抗肿瘤反应。为了克服 DC 疫苗治疗所需的 DC 数量和质量问题，我们专注于诱导多能干细胞（iPSCs）作为获得 DC 的新工具，并报告了 iPSCs 衍生的 DC（iPSDC）的疗效。然而，在 iPSDC 疫苗治疗的临床应用中，需要进一步增强其抗肿瘤效果。在这项研究中，我们将间皮素（MSLN）作为一种潜在有用的 TAA，并且专注于泛素-蛋白酶体系统来增强 iPSDC 的抗原呈递能力。来自健康供体的转导 MSLN 基因的 iPSDC（iPSDCs-MSLN）诱导的 CTL 对表达 MSLN 的自体淋巴母细胞样细胞（LCLs）-MSLN 显示出细胞毒性活性。转导泛素-MSLN 融合基因的 iPSDC 诱导的 CTL 对 LCLs-MSLN 的细胞毒性活性高于转导 MSLN 的 iPSDC 诱导的 CTL。本研究旨在通过同时表达泛素和 MSLN 的基因修饰 iPSDC 的免疫接种来克服外周 T 细胞对 MSLN 的耐受性，从而对内源性表达 MSLN 的肿瘤产生强烈的细胞毒性。因此，该策略可能有望作为一种有效的癌症疫苗治疗方法在临床上得到应用。
