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

Abstract

<div>Abstract<p>Recent studies have shown that stem cell memory T (T<sub>SCM</sub>) cell-like properties are important for successful adoptive immunotherapy 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 (iT<sub>SCM</sub>) cells by coculture with stromal OP9 cells expressing the NOTCH ligand. However, the mechanism of NOTCH-mediated iT<sub>SCM</sub> reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converted conventional human CAR-T cells into T<sub>SCM</sub>-like CAR-T, “CAR-iT<sub>SCM</sub>” cells, and that mitochondrial metabolic reprogramming played a key role in this conversion. NOTCH signaling promoted mitochondrial biogenesis and fatty acid synthesis during iT<sub>SCM</sub> formation, which are essential for the properties of iT<sub>SCM</sub> cells. Forkhead box M1 (FOXM1) was identified as a downstream target of NOTCH, which was responsible for these metabolic changes and the subsequent iT<sub>SCM</sub> differentiation. Like NOTCH-induced CAR-iT<sub>SCM</sub> cells, FOXM1-induced CAR-iT<sub>SCM</sub> cells possessed superior antitumor potential compared with conventional CAR-T cells. We propose that NOTCH- or FOXM1-driven CAR-iT<sub>SCM</sub> formation is an effective strategy for improving cancer immunotherapy.</p>Significance:<p>Manipulation of signaling and metabolic pathways important for directing production of stem cell memory–like T cells may enable development of improved CAR-T cells.</p></div>