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

Cell Reports (Mar 2018)

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

Journal volume & issue: Vol. 22, no. 12
pp. 3175 – 3190

Abstract

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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

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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