The NOTCH–FOXM1 axis plays a key role in mitochondrial biogenesis in the induction of human stem cell memory–like CAR-T cells

Taisuke Kondo, Makoto Ando, Nao Nagai, Wataru Tomisato, Tanakorn Srirat, Binbin Liu, Setsuko Mise-Omata, Mari Ikeda, Shunsuke Chikuma, Hiroshi Nishimasu, Osamu Nureki, Mitsuyo Ohmura, Noriyo Hayakawa, Takako Hishiki, Ryosuke Uchibori, Keiya Ozawa, Akihiko Yoshimura

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Abstract

Recent studies have shown that stem cell memory T (TSCM) cell-like properties are important for successful adoptive immunotherapy by the chimeric antigen receptor–engineered-T (CART) cells. We previously reported that both human and murineactivated T cells are converted into stem cell memory-like T (iTSCM) cells by coculture with stromal OP9 cells expressing the NOTCH ligand. However, the mechanism of NOTCH-mediated iTSCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converted conventional human CAR-T cells into TSCM-like CAR-T, “CAR-iTSCM” cells, and that mitochondrial metabolic reprogramming played a key role in this conversion. NOTCH signaling promoted mitochondrial biogenesis and fatty acid synthesis during iTSCM formation, which are essential for the properties of iTSCM cells. Forkhead box M1 (FOXM1) was identified as a downstream target of NOTCH, which was responsible for these metabolic changes and the subsequent iTSCM differentiation. Like NOTCH-induced CAR-iTSCM cells, FOXM1-induced CAR-iTSCM cells possessed superior antitumor potential compared with conventional CAR-T cells. We propose that NOTCH-or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy.

Original languageEnglish
Pages (from-to)471-483
Number of pages13
JournalCancer Research
Volume80
Issue number3
DOIs
Publication statusPublished - 2020 Feb 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kondo, T., Ando, M., Nagai, N., Tomisato, W., Srirat, T., Liu, B., Mise-Omata, S., Ikeda, M., Chikuma, S., Nishimasu, H., Nureki, O., Ohmura, M., Hayakawa, N., Hishiki, T., Uchibori, R., Ozawa, K., & Yoshimura, A. (2020). The NOTCH–FOXM1 axis plays a key role in mitochondrial biogenesis in the induction of human stem cell memory–like CAR-T cells. Cancer Research, 80(3), 471-483. https://doi.org/10.1158/0008-5472.CAN-19-1196