| Literature DB >> 30449714 |
Atsutaka Minagawa1, Toshiaki Yoshikawa2, Masaki Yasukawa3, Akitsu Hotta4, Mihoko Kunitomo5, Shoichi Iriguchi6, Maiko Takiguchi5, Yoshiaki Kassai5, Eri Imai7, Yutaka Yasui7, Yohei Kawai7, Rong Zhang2, Yasushi Uemura2, Hiroyuki Miyoshi8, Mahito Nakanishi9, Akira Watanabe4, Akira Hayashi5, Kei Kawana10, Tomoyuki Fujii11, Tetsuya Nakatsura2, Shin Kaneko12.
Abstract
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.Entities:
Keywords: CD8 T cell; HLA matched iPS cell; T cell differentiation; T cell-derived iPS cell; TCR gene therapy; TCR rearrangement; antigen-specific T cell regeneration; cancer immunotherapy; cytotoxic T cell; iPS cell bank
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Year: 2018 PMID： 30449714 DOI： 10.1016/j.stem.2018.10.005
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633