Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System
Raul Vizcardo,
Nicholas D. Klemen,
S.M. Rafiqul Islam,
Devikala Gurusamy,
Naritaka Tamaoki,
Daisuke Yamada,
Haruhiko Koseki,
Benjamin L. Kidder,
Zhiya Yu,
Li Jia,
Amanda N. Henning,
Meghan L. Good,
Marta Bosch-Marce,
Takuya Maeda,
Chengyu Liu,
Zied Abdullaev,
Svetlana Pack,
Douglas C. Palmer,
David F. Stroncek,
Fumito Ito,
Francis A. Flomerfelt,
Michael J. Kruhlak,
Nicholas P. Restifo
Affiliations
Raul Vizcardo
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Corresponding author
Nicholas D. Klemen
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
S.M. Rafiqul Islam
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Devikala Gurusamy
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Naritaka Tamaoki
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Daisuke Yamada
Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Science, Yokohama, Kanagawa 230-0045, Japan
Haruhiko Koseki
Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Science, Yokohama, Kanagawa 230-0045, Japan
Benjamin L. Kidder
Department of Oncology and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
Zhiya Yu
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Li Jia
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Amanda N. Henning
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Meghan L. Good
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Marta Bosch-Marce
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Takuya Maeda
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Chengyu Liu
Transgenic Core, Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA
Zied Abdullaev
Experimental Pathology Laboratory, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Svetlana Pack
Experimental Pathology Laboratory, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Douglas C. Palmer
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA
David F. Stroncek
Department of Transfusion Medicine Department, Clinical Center, NIH, Bethesda, MD 20892, USA
Fumito Ito
Department of Surgical Oncology, Roswell Park Cancer Center, Buffalo, NY 14263, USA; Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Francis A. Flomerfelt
Experimental Transplantation and Immunology Branch, NIH Clinical Center, NIH, Bethesda, MD 20892, USA
Michael J. Kruhlak
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Nicholas P. Restifo
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Corresponding author
Summary: 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. : A barrier for clinical application of iPSC-derived CD8 T cells using OP9/DLL1 is their abnormal biology. Vizcardo et al. show that a 3D thymic culture system enables the generation of a homogeneous antigen-specific T cell subset, named iTEs, which closely mimics naive T cells and exhibits potent anti-tumor activity. Keywords: thymopoiesis, T cell differentiation, iPSC differentiation, adoptive cell transfer, naïve T cell, recent rhymic emigrants, fetal thymus organ culture, immunotherapy, 3D culture, tumor antigen specific T cell
