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.

中文翻译：

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表达OX40配体的诱导性多能干细胞衍生的骨髓细胞在晚期黑素瘤中扩增抗原特异性T细胞。

免疫检查点抑制剂可提高不可切除黑色素瘤患者的生存率。但是，有些患者没有反应，并且已报告了多种与免疫相关的不良事件。因此，迫切需要更有效且具有抗原特异性的免疫疗法。我们以前曾报道过使用诱导多能干细胞（iPS-ML）衍生的永生髓细胞进行免疫细胞疗法的功效。在这项研究中，我们生成了过表达OX40L的iPS-ML（iPS-ML-Zsgreen-OX40L），并研究了它们的特性和体内抗小鼠黑色素瘤的功效。我们发现iPS‐ML‐Zsgreen‐OX40L抑制了B16‐BL6黑色素瘤的进展，并延长了表达卵清蛋白（OVA）的B16黑色素瘤（MO4）的小鼠的存活期。抗原特异性CD8 ^+的数量用OVA肽脉冲的iPS-ML-Zsgreen-OX40L处理的脾细胞中的T细胞高于未使用OX40L的脾细胞。OVA肽脉冲的iPS-ML-Zsgreen-OX40L显着增加了MO4肿瘤中的肿瘤浸润T淋巴细胞（TIL）的数量。流式细胞仪显示，TIL中调节性T细胞减少，但效应子和效应器记忆T细胞增加。尽管我们计划在临床应用中使用同种异体iPS-ML，但iPS-ML在同系小鼠模型中显示出了致癌性。整合自杀基因对于确保未来研究的安全性是必要的。总的来说，这些结果表明，iPS-ML-Zsgreen-OX40L治疗可能是抗原特异性癌症免疫治疗的一种新方法。