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GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy

ABSTRACT: GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy

PROVIDER: PRJNA1104654 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28807967_1.fastq.gz	Fastqsanger.gz
	SRR28807967_2.fastq.gz	Fastqsanger.gz
	SRR28807968_1.fastq.gz	Fastqsanger.gz
	SRR28807968_2.fastq.gz	Fastqsanger.gz
	SRR28807969_1.fastq.gz	Fastqsanger.gz

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GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy

Project description:The tumor microenvironment presents many obstacles to effective CAR T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Ra2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes Tscm formation and prolongs survival. RNA sequencing of these CAR T cells reveals that overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR T cells improve tumor control and response to rechallenge in an RCC patient derived xenograft model. Furthermore, IL13Ra2-BBz CAR T cells overexpressing GLUT1 prolong survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR T cells in harsh tumor environments where glucose is limiting.

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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_TCF7_OE_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_FOXO1OE_stimulation/rest_RNAseq]

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

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Overexpression of FOXO1 enhances CAR T cell polyfunctionality, metabolic fitness and efficacy against solid tumors

Project description:Overexpression of FOXO1 enhances CAR T cell polyfunctionality, metabolic fitness and efficacy against solid tumors

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GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency

Project description:The intensive nutrient requirements needed to sustain T cell activation and proliferation combined with competition for nutrients within the tumor microenvironment raise the prospect that glucose availability may limit CAR T cell function. Here, we sought to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observed that GLUT1OE in CAR-T cells increased glucose consumption, glycolysis, glycolytic reserve and oxidative phosphorylation and these effects were associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induced broad metabolic reprogramming associated with increased glutathione41 mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secreted more proinflammatory cytokines and mediated enhanced cytotoxicity in vitro and demonstrated superior tumor control and persistence in vivo. Our collective findings support a model wherein glucose availability is rate limiting for optimal effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE provides a new approach to augment antitumor immune function.

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Overexpression of FOXO1 enhances CAR T cell polyfunctionality, metabolic fitness and efficacy against solid tumors [Mouse RNAseq]

Project description:Overexpression of FOXO1 enhances CAR T cell polyfunctionality, metabolic fitness and efficacy against solid tumors [Mouse RNAseq]

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A culture method with berbamine, a plant alkaloid, enhances CAR-T cell efficacy through modulating cellular metabolism

Project description:Memory T cells demonstrate superior in vivo persistence and antitumor efficacy. However, methods for manufacturing less differentiated T cells are not yet well-established. Here, we show that producing chimeric antigen receptor (CAR)-T cells using berbamine (BBM), a natural compound found in the Chinese herbal medicine Berberis amurensis, enhances the antitumor efficacy of CAR-T cells. BBM is identified through cell-based screening of chemical compounds using induced pluripotent stem cell-derived T cells, leading to improved viability with a memory T cell phenotype. Transcriptomics and metabolomics using stem cell memory T cells reveal that BBM broadly enhances lipid metabolism. Furthermore, the addition of BBM downregulates the phosphorylation of p38 mitogen-activated protein kinase and enhanced mitochondrial respiration. CD19-CAR-T cells cultured with BBM also extend the survival of leukaemia mouse models due to their superior in vivo persistence. This technology offers a straightforward approach to enhancing the antitumor efficacy of CAR-T cells.

2024-05-02 | GSE264206 | GEO

Overexpression of FOXO1 enhances CAR T cell polyfunctionality, metabolic fitness and efficacy against solid tumors [Human RNAseq CD8]

Project description:Overexpression of FOXO1 enhances CAR T cell polyfunctionality, metabolic fitness and efficacy against solid tumors [Human RNAseq CD8]

| PRJNA936110 | ENA

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