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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_TCF7_OE_RNAseq]

ABSTRACT: Investigating the transcriptional profile of human FOXO1 or TCF7 overexpressing α-lewisY CAR T cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE263162 | GEO | 2024/05/08

REPOSITORIES: GEO

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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1OE_stimulation/rest_RNAseq]

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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_scRNAseq]

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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_TCF7_OE_RNAseq]

Project description:FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_TCF7_OE_RNAseq]

| PRJNA1095997 | ENA

FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_scRNAseq]

Project description:FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_scRNAseq]

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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1OE_stimulation/rest_RNAseq]

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FOXO1 is a master regulator of CAR T memory programming [scRNA_FOXO1_NGFR]

Project description:Poor CAR T persistence limits CAR T cell therapies for B cell malignancies and solid tumors1,2. The expression of memory-associated genes such as TCF7 (protein name TCF1) is linked to response and long-term persistence in patients3–7, thereby implicating memory programs in therapeutic efficacy. Here, we demonstrate that the pioneer transcription factor, FOXO1, is responsible for promoting memory programs and restraining exhaustion in human CAR T cells. Pharmacologic inhibition or gene editing of endogenous FOXO1 in human CAR T cells diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype, and impaired antitumor activity in vitro and in vivo. FOXO1 overexpression induced a gene expression program consistent with T cell memory and increased chromatin accessibility at FOXO1 binding motifs. FOXO1-overexpressing cells retained function, memory potential, and metabolic fitness during settings of chronic stimulation and exhibited enhanced persistence and antitumor activity in vivo. In contrast, TCF1 overexpression failed to enforce canonical memory programs or enhance CAR T cell potency. Importantly, endogenous FOXO1 activity correlated with CAR T and TIL responses in patients, underscoring its clinical relevance in cancer immunotherapy. Our results demonstrate that memory reprogramming through FOXO1 can enhance the persistence and potency of human CAR T cells and highlights the utility of pioneer factors, which bind condensed chromatin and induce local epigenetic remodeling, for optimizing therapeutic T cell states.

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