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  3. Human iPSC-derived CD4+ Treg-like cells engineered with chimeric antigen receptors control GvHD in a xenograft model

Human iPSC-derived CD4+ Treg-like cells engineered with chimeric antigen receptors control GvHD in a xenograft model

  • Cell Stem Cell. 2024 Jun 6;31(6):795-802.e6. doi: 10.1016/j.stem.2024.05.004.
Hisashi Yano 1,  Keiko Koga 2,  Takayuki Sato 2,  Tokuyuki Shinohara 2,  Shoichi Iriguchi 3,  Atsushi Matsuda 2,  Kazuki Nakazono 2,  Maki Shioiri 2,  Yasuyuki Miyake 3,  Yoshiaki Kassai 2,  Hitoshi Kiyoi 4,  Shin Kaneko 5
Affiliations

Affiliations

  • 1 Shin Kaneko Laboratory, CiRA, Kyoto University, Kyoto, Japan; Takeda-CiRA joint research program (T-CiRA), Fujisawa, Kanagawa, Japan; Department of Haematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • 2 Takeda-CiRA joint research program (T-CiRA), Fujisawa, Kanagawa, Japan; T-CiRA Discovery, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa, Japan.
  • 3 Shin Kaneko Laboratory, CiRA, Kyoto University, Kyoto, Japan; Takeda-CiRA joint research program (T-CiRA), Fujisawa, Kanagawa, Japan.
  • 4 Department of Haematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • 5 Shin Kaneko Laboratory, CiRA, Kyoto University, Kyoto, Japan; Takeda-CiRA joint research program (T-CiRA), Fujisawa, Kanagawa, Japan. Electronic address: kaneko.shin@cira.kyoto-u.ac.jp.
PMID: 38848686 DOI: 10.1016/j.stem.2024.05.004
Abstract

CD4+ T cells induced from human iPSCs (iCD4+ T cells) offer a therapeutic opportunity for overcoming immune pathologies arising from hematopoietic stem cell transplantation. However, most iCD4+ T cells are conventional helper T cells, which secrete inflammatory cytokines. We induced high-level expression of FOXP3, a master transcription factor of regulatory T cells, in iCD4+ T cells. Human iPSC-derived, FOXP3-induced CD4+ T (iCD4+ Treg-like) cells did not secrete inflammatory cytokines upon activation. Moreover, they showed demethylation of the Treg-specific demethylation region, suggesting successful conversion to immunosuppressive iCD4+ Treg-like cells. We further assessed these iCD4+ Treg-like cells for CAR-mediated immunosuppressive ability. HLA-A2 CAR-transduced iCD4+ Treg-like cells inhibited CD8+ cytotoxic T cell (CTL) division in a mixed lymphocyte reaction assay with A2+ allogeneic CTLs and suppressed xenogeneic graft-versus-host disease (GVHD) in NSG mice treated with A2+ human PBMCs. In most cases, these cells suppressed the xenogeneic GvHD progression as much as natural CD25+CD127- Tregs did.

Keywords

graft-versus-host disease; induced pluripotent stem cells; regulatory T cells.

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