Generation and application of human induced-stem cell memory T cells for adoptive immunotherapy

Taisuke Kondo, Yuki Imura, Shunsuke Chikuma, Sana Hibino, Setsuko Omata-Mise, Makoto Ando, Takashi Akanuma, Mana Iizuka, Ryota Sakai, Rimpei Morita, Akihiko Yoshimura

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Adoptive T-cell therapy is an effective strategy for cancer immunotherapy. However, infused T cells frequently become functionally exhausted, and consequently offer a poor prognosis after transplantation into patients. Adoptive transfer of tumor antigen-specific stem cell memory T (TSCM) cells is expected to overcome this shortcoming as TSCM cells are close to naïve T cells, but are also highly proliferative, long-lived, and produce a large number of effector T cells in response to antigen stimulation. We previously reported that activated effector T cells can be converted into TSCM-like cells (iTSCM) by coculturing with OP9 cells expressing Notch ligand, Delta-like 1 (OP9-hDLL1). Here we show the methodological parameters of human CD8+ iTSCM cell generation and their application to adoptive cancer immunotherapy. Regardless of the stimulation by anti-CD3/CD28 antibodies or by antigen-presenting cells, human iTSCM cells were more efficiently induced from central memory type T cells than from effector memory T cells. During the induction phase by coculture with OP9-hDLL1 cells, interleukin (IL)-7 and IL-15 (but not IL-2 or IL-21) could efficiently generate iTSCM cells. Epstein–Barr virus-specific iTSCM cells showed much stronger antitumor potentials than conventionally activated T cells in humanized Epstein–Barr virus transformed-tumor model mice. Thus, adoptive T-cell therapy with iTSCM offers a promising therapeutic strategy for cancer immunotherapy.

Original languageEnglish
Pages (from-to)2130-2140
Number of pages11
JournalCancer science
Volume109
Issue number7
DOIs
Publication statusPublished - 2018 Jul

Keywords

  • Epstein–Barr virus
  • adoptive immunotherapy
  • cytokine
  • immunological memory
  • methodological study

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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