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

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8 Antigens / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Humans
  • Immunotherapy*
  • Induced Pluripotent Stem Cells / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / immunology*
  • Tumor Cells, Cultured


  • CD8 Antigens
  • CD8alphabeta antigen
  • Receptors, Antigen, T-Cell