Journal
CELL STEM CELL
Volume 23, Issue 6, Pages 850-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2018.10.005
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Funding
- Ministry of Education, Culture, Sports, Science and Technology Japan [23591413, 15H04655, 15J05263, 26293357]
- Japan Agency for Medical Research and Development (Project for Development of Innovative Research on Cancer Therapeutics, Practical Research for Innovative Cancer Control, and Core Center for iPS Cell Research)
- National Cancer Center Research Fund
- Takeda-CiRA collaboration program
- Thyas Co., Ltd.
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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 CD8 alpha 8 T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) alpha 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 CD8 alpha 8 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 CD8 alpha 8 T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.
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