Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: UMLS:C0406810 (
NAME
)
13,345
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Recent studies have shown that stem cell memory T (T
SCM
) 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
SCM
) cells by coculture with stromal OP9 cells expressing the NOTCH ligand. However, the mechanism of NOTCH-mediated iT
SCM
reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converted conventional human
CAR
-T cells into T
SCM
-like
CAR
-T, "CAR-iT
SCM
" cells, and that mitochondrial metabolic reprogramming played a key role in this conversion. NOTCH signaling promoted mitochondrial biogenesis and fatty acid synthesis during iT
SCM
formation, which are essential for the properties of iT
SCM
cells.
Forkhead box M1
(
FOXM1
) was identified as a downstream target of NOTCH, which was responsible for these metabolic changes and the subsequent iT
SCM
differentiation. Like NOTCH-induced
CAR
-iT
SCM
cells,
FOXM1
-induced
CAR
-iT
SCM
cells possessed superior antitumor potential compared with conventional
CAR
-T cells. We propose that NOTCH- or
FOXM1
-driven
CAR
-iT
SCM
formation is an effective strategy for improving cancer immunotherapy. SIGNIFICANCE: 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.
...
PMID:The NOTCH-FOXM1 Axis Plays a Key Role in Mitochondrial Biogenesis in the Induction of Human Stem Cell Memory-like CAR-T Cells. 3176 27
