Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Japan.
Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
Cell Stem Cell. 2018 Dec 6;23(6):850-858.e4. doi: 10.1016/j.stem.2018.10.005. Epub 2018 Nov 15.
Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8αβ T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) α chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8αβ T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.
T 细胞的可用性有限，增殖耗竭是成功进行基于 T 细胞的免疫疗法的主要障碍，而通过使用源自抗原特异性 T 细胞（T-iPSCs）的“更新”诱导多能干细胞，可能克服这些障碍。然而，安全有效的 T 细胞免疫疗法需要严格的抗原特异性。在这里，我们报告称，在体外分化的 CD4/CD8 双阳性阶段，人 T-iPSCs 中的 CD8αβ T 细胞通过 T 细胞受体（TCR）α 链基因的额外重排而丧失其抗原特异性。在 T-iPSCs 中敲除重组酶基因可防止这种额外的 TCR 重排。此外，当从转导了抗原特异性 TCR 的单核细胞衍生的 iPSCs 分化出 CD8αβ T 细胞时，它们表现出转导 TCR 的单克隆表达。TCR 稳定的再生 CD8αβ T 细胞可有效抑制异种移植癌症模型中的肿瘤生长。这些方法可能有助于安全有效的再生 T 细胞免疫疗法。
