Induced pluripotent stem cell-derived myeloid cells expressing OX40 ligand amplify antigen-specific T cells in advanced melanoma
Induced pluripotent stem cell-derived myeloid cells expressing OX40 ligand amplify antigen-specific T cells in advanced melanoma
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DOI：
10.1111/pcmr.12887
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发表时间：
2020-05-18
影响因子：
4.3
通讯作者：
Ihn, Hironobu
中科院分区：
文献类型：
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作者：
Kimura, Toshihiro;Fukushima, Satoshi;Ihn, Hironobu
免疫检查点抑制剂提高了不可切除黑色素瘤患者的生存率。然而，一些患者没有反应，并且已经报告了可变的免疫相关不良事件。因此，迫切需要更有效和抗原特异性的免疫疗法。我们先前报道了用来自诱导多能干细胞（iPS-ML）的永生化骨髓细胞进行免疫细胞疗法的功效。在这项研究中，我们产生了OX 40 L-过表达iPS-ML（iPS-ML-Zsgreen-OX 40 L），并研究了它们的特性和对小鼠黑色素瘤的体内功效。我们发现iPS-ML-Zsgreen-OX 40 L抑制了B16-BL 6黑色素瘤的进展，并延长了表达卵清蛋白（OVA）的B16黑色素瘤（MO 4）小鼠的生存期。在用OVA肽脉冲的iPS-ML-Zsgreen-OX 40 L处理的脾细胞中，抗原特异性CD 8（+）T细胞的数量高于没有OX 40 L的那些。OVA肽脉冲的iPS-ML-Zsgreen-OX 40 L显著增加了MO 4肿瘤中肿瘤浸润T淋巴细胞（TIL）的数量。流式细胞术显示TIL中调节性T细胞减少，但效应T细胞和效应记忆T细胞增加。虽然我们计划在临床应用中使用同种异体iPS-ML，但iPS-ML在同基因小鼠模型中显示出致瘤性。为了保证今后研究的安全性，有必要对自杀基因进行验证。总的来说，这些结果表明iPS-ML-Zsgreen-OX 40 L疗法可能是抗原特异性癌症免疫治疗的新方法。
Immune checkpoint inhibitors improved the survival rate of patients with unresectable melanoma. However, some patients do not respond, and variable immune-related adverse events have been reported. Therefore, more effective and antigen-specific immune therapies are urgently needed. We previously reported the efficacy of an immune cell therapy with immortalized myeloid cells derived from induced pluripotent stem cells (iPS-ML). In this study, we generated OX40L-overexpressing iPS-ML (iPS-ML-Zsgreen-OX40L) and investigated their characteristics and in vivo efficacy against mouse melanoma. We found that iPS-ML-Zsgreen-OX40L suppressed the progression of B16-BL6 melanoma, and prolonged survival of mice with ovalbumin (OVA)-expressing B16 melanoma (MO4). The number of antigen-specific CD8(+) T cells was higher in spleen cells treated with OVA peptide-pulsed iPS-ML-Zsgreen-OX40L than in those without OX40L. The OVA peptide-pulsed iPS-ML-Zsgreen-OX40L significantly increased the number of tumor-infiltrating T lymphocytes (TILs) in MO4 tumor. Flow cytometry showed decreased regulatory T cells but increased effector and effector memory T cells among the TILs. Although we plan to use allogeneic iPS-ML in the clinical applications, iPS-ML showed the tumorgenicity in the syngeneic mice model. Incorporating the suicide gene is necessary to ensure the safety in the future study. Collectively, these results indicate that iPS-ML-Zsgreen-OX40L therapy might be a new method for antigen-specific cancer immunotherapy.