Format

Send to

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

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

Author information

1
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: vizcardo@nih.gov.
2
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
3
Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Science, Yokohama, Kanagawa 230-0045, Japan.
4
Department of Oncology and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
5
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
6
Transgenic Core, Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
7
Experimental Pathology Laboratory, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
8
Department of Transfusion Medicine Department, Clinical Center, NIH, Bethesda, MD 20892, USA.
9
Department of Surgical Oncology, Roswell Park Cancer Center, Buffalo, NY 14263, USA; Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
10
Experimental Transplantation and Immunology Branch, NIH Clinical Center, NIH, Bethesda, MD 20892, USA.
11
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
12
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: restifo@nih.gov.

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

PMID:
29562175
PMCID:
PMC5930030
DOI:
10.1016/j.celrep.2018.02.087
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center