Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Japan.
Nat Commun. 2021 Jan 18;12(1):430. doi: 10.1038/s41467-020-20658-3.
Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of "off-the-shelf" T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce "off-the-shelf" and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.
嵌合抗原受体 T 细胞免疫疗法的临床成功促进了针对多种疾病的 T 细胞免疫疗法的进一步发展。一种方法是开发“现货供应”的 T 细胞来源。从多能干细胞 (PSCs) 生成 T 细胞的技术可能为生产“现货供应”和合成同种异体 T 细胞提供平台。然而，目前方法的低分化效率和较差的可扩展性可能会影响其效用。在这里，我们展示了从抗原特异性细胞毒性 T 细胞克隆或 TCR 转导的 iPSC 作为起始材料的诱导多能干细胞 (iPSC) 中 T 细胞的分化效率得到了提高。我们还描述了无饲养细胞的分化培养系统，该系统跨越 iPSC 维持到 T 细胞增殖阶段，能够大规模生产再生 T 细胞。此外，在 T 细胞分化过程中同时添加 SDF1α 和 p38 抑制剂可增强 T 细胞的定向分化。再生 T 细胞在体外显示 TCR 依赖性功能，并具有体内抗肿瘤活性。该系统为大量再生 T 细胞的临床应用以及研究人类 T 细胞分化和生物学提供了一个平台。
