Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

Cell Rep. 2018 Mar 20;22(12):3175-3190. doi: 10.1016/j.celrep.2018.02.087.

Abstract

Induced pluripotent stem cell (iPSC)-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4+CD8+ double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8αβ+ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs). iTEs exhibit phenotypic and functional similarities to naive T cells both in vitro and in vivo, including the capacity for expansion, memory formation, and tumor suppression. These data illustrate the limitations of current methods and provide a tool to develop the next generation of iPSC-based antigen-specific immunotherapies.

Keywords: 3D culture; T cell differentiation; adoptive cell transfer; fetal thymus organ culture; iPSC differentiation; immunotherapy; naïve T cell; recent rhymic emigrants; thymopoiesis; tumor antigen specific T cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Culture Techniques / methods
  • Cell Differentiation / physiology
  • Humans
  • Imaging, Three-Dimensional / methods*
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / immunology
  • Induced Pluripotent Stem Cells / metabolism
  • Thymus Gland / cytology*
  • Thymus Gland / diagnostic imaging
  • Thymus Gland / immunology