TY - JOUR
T1 - The NOTCH–FOXM1 axis plays a key role in mitochondrial biogenesis in the induction of human stem cell memory–like CAR-T cells
AU - Kondo, Taisuke
AU - Ando, Makoto
AU - Nagai, Nao
AU - Tomisato, Wataru
AU - Srirat, Tanakorn
AU - Liu, Binbin
AU - Mise-Omata, Setsuko
AU - Ikeda, Mari
AU - Chikuma, Shunsuke
AU - Nishimasu, Hiroshi
AU - Nureki, Osamu
AU - Ohmura, Mitsuyo
AU - Hayakawa, Noriyo
AU - Hishiki, Takako
AU - Uchibori, Ryosuke
AU - Ozawa, Keiya
AU - Yoshimura, Akihiko
N1 - Funding Information:
We thank Yoshiko Noguchi, Yasuko Hirata, Yukiko Tokifuji, Mika Inoue, Eiji Sugihara, Hideyuki Saya (Keio University) for their technical assistance and Taeka Hayakawa and Yutaka Kawakami (Keio University) for discussions. This work was supported by JSPS KAKENHI (S) JP17H06175, Challenging Research (P) JP18H05376, and AMED-CREST JP19gm1110009, TaNeDS grant program (Daiichi Sankyo Co., Ltd.), the Takeda Science Foundation, the Uehara Memorial Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Bristol–Myers Squibb Research grant, the Kanae Foundation, the SENSHIN Medical Research Foundation and the Keio Gijuku Academic Developmental Funds.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-1196
DO - 10.1158/0008-5472.CAN-19-1196
M3 - Article
C2 - 31767627
AN - SCOPUS:85076397951
SN - 0008-5472
VL - 80
SP - 471
EP - 483
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -
