title: Regeneration of CD8αβ T Cells from T-cell-Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity.
abstract: Although adoptive transfer of cytotoxic T lymphocytes (CTL) offer a promising cancer therapeutic direction, the generation of antigen-specific CTL from patients has faced difficulty in efficient expansion in ex vivo culture. To resolve this issue, several groups have proposed that induced pluripotent stem cell technology be applied for the expansion of antigen-specific CTL, which retain expression of the same T-cell receptor as original CTL. However, in these previous studies, the regenerated CTL are mostly of the CD8αα+innate type and have less antigen-specific cytotoxic activity than primary CTL. Here we report that, by stimulating purified iPSC-derived CD4/CD8 double-positive cells with anti-CD3 antibody, T cells expressing CD8αβ were generated and exhibited improved antigen-specific cytotoxicity compared with CD8αα+CTL. Failure of CD8αβ T-cell production using the previous method was found to be due to killing of double-positive cells by the double-negative cells in the mixed cultures. We found that WT1 tumor antigen-specific CTL regenerated by this method prolonged the survival of mice bearing WT1-expressing leukemic cells. Implementation of our methods may offer a useful clinical tool. Cancer Res; 76(23); 6839-50. ©2016 AACR.
authors.affiliation: Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.|Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.|Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nagano
authors.affiliation: Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichise
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Laboratory for Developmental Genetics, Riken Center for Integrative Medical Science (IMS), Yokohama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Laboratory for Developmental Genetics, Riken Center for Integrative Medical Science (IMS), Yokohama, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitawaki
authors.affiliation: Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculity of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Kadowaki
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.affiliation: Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. kawamoto@frontier.kyoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000235:genetics*; D006801:Humans; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059467:Transcriptome / Q000235:genetics*
chemical_list: D016827:CD8 Antigens; C433839:CD8alphabeta antigen