Zhang Minggang, Zhao Zeguo, Pritykin Yuri, Hannum Margaret, Scott Andrew C, Kuo Fengshen, Sanghvi Viraj, Chan Timothy A, Seshan Venkatraman, Wendel Hans-Guido, Schietinger Andrea, Sadelain Michel, Huse Morgan
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sci Transl Med. 2021 Sep 15;13(611):eabg4328. doi: 10.1126/scitranslmed.abg4328.
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, , 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.
过继性T细胞疗法（ACT）是一种很有前景的癌症治疗策略，但由于细胞内在的调控程序会限制T细胞功能的程度或持续时间，该疗法常常失败。在本研究中，我们发现，在多个小鼠模型中，异位表达微小RNA-200c（miR-200c）可在ACT过程中显著增强CD8细胞毒性T淋巴细胞（CTL）的抗肿瘤活性。用miR-200c转导的CTL在植入过程中凋亡减少，体内持久性增强，同时转录调节因子T细胞因子1（TCF1）和炎性细胞因子肿瘤坏死因子（TNF）上调。miR-200c通过抑制转录因子Zeb1从而诱导上皮细胞特征性基因来引发这些变化。这些基因之一EpCAM的过表达足以增强治疗性T细胞对实体瘤和液体肿瘤的反应。这些结果确定了miR-200c–EpCAM轴是改善ACT的一条途径，并证明特定的基因扰动可产生具有有利治疗特性的表型不同的T细胞。
