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Cancer Res. 2019 Nov 25. pii: canres.1196.2019. doi: 10.1158/0008-5472.CAN-19-1196. [Epub ahead of print]

The NOTCH-FOXM1 Axis Plays a Key Role in Mitochondrial Biogenesis in the Induction of Human Stem Cell Memory-like CAR-T Cells.

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Microbiology and Immunology, School of Medicine, Keio University.
Department of Microbiology and Immunology, School of Medicine, Keio University.
Cell Therapy Research Laboratories, Daiichi Sankyo Co., Ltd.
Microbiology and Immunology, Keio University School of Medicine.
University of Tokyo.
Department of Biochemistry, Department of Biochemistry, School of Medicine.
Exploratory Research for Advanced Technology (ERATO) Suematsu Gas Biology Project, Japan Science and Technology Agency.
School of Medicine, Keio University.
Division of Immuno- Gene & Cell Therapy (Takara Bio), Jichi Medical University.
Division of Immuno-Gene & Cell Therapy (Takara Bio), Jichi Medical University.
Microbiology and Immunology, School of Medicine, Keio University


Recent studies have shown that stem cell memory T (TSCM) cell-like properties are important for successful adoptive immune therapy by the chimeric antigen receptor-engineered-T (CAR-T) cells. We previously reported that both human and murine activated T cells are converted into stem cell memory-like T (iTSCM) cells by co-culture 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 to conventional CAR-T cells. We propose that NOTCH- or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy.

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