Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy

• DOI: 10.1016/j.stem.2018.10.005
• Publication Date: 2018-11-15T16:43:13Z
• Authors: Atsutaka Minagawa; Toshiaki Yoshikawa; Masaki Yasukawa; Akitsu Hotta; Mihoko Kunitomo; Shoichi Iriguchi; Maiko Takiguchi; Yoshiaki Kassai; Eri Imai; Yutaka Yasui; Yohei Kawai; Rong Zhang; Yasushi Uemura; Hiroyuki Miyoshi; Mahito Nakanishi; Akira Watanabe; Akira Hayashi; Kei Kawana; Tomoyuki Fujii; Tetsuya Nakatsura; Shin Kaneko
• Keywords: Cancer Immunotherapy

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.