Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8⁺ cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF). miR-200c elicited these changes by suppressing the transcription factor Zeb1 and thereby inducing genes characteristic of epithelial cells. Overexpression of one of these genes, Epcam, was sufficient to augment therapeutic T cell responses against both solid and liquid tumors. These results identify the miR-200c–EpCAM axis as an avenue for improving ACT and demonstrate that select genetic perturbations can produce phenotypically distinct T cells with advantageous therapeutic properties.

中文翻译：

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miR-200c-EpCAM 轴的异位激活增强过继细胞治疗模型中的抗肿瘤 T 细胞反应

过继性 T 细胞疗法 (ACT) 是一种很有前途的癌症治疗策略，但由于细胞内在调节程序限制了 T 细胞功能的程度或持续时间，它经常失败。在这项研究中，我们发现 microRNA-200c (miR-200c) 的异位表达显着增强了多个小鼠模型在 ACT 期间CD8 ^{+细胞毒性 T 淋巴细胞 (CTL) 的抗肿瘤活性。}用 miR-200c 转导的 CTL 在移植期间表现出细胞凋亡减少和体内持久性增强，伴随着转录调节因子 T 细胞因子 1 (TCF1) 和炎性细胞因子肿瘤坏死因子 (TNF) 的上调。miR-200c 通过抑制转录因子 Zeb1 引发这些变化，从而诱导上皮细胞的基因特征。这些基因之一的过度表达，Epcam足以增强针对实体和液体肿瘤的治疗性 T 细胞反应。这些结果将 miR-200c-EpCAM 轴确定为改善 ACT 的途径，并证明选择的遗传扰动可以产生具有有利治疗特性的表型不同的 T 细胞。