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Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function

ABSTRACT: Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function

PROVIDER: PRJNA934314 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23440557_1.fastq.gz	Fastqsanger.gz
	SRR23440557_2.fastq.gz	Fastqsanger.gz
	SRR23440558_1.fastq.gz	Fastqsanger.gz
	SRR23440558_2.fastq.gz	Fastqsanger.gz
	SRR23440559_1.fastq.gz	Fastqsanger.gz

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Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function [DNA-edit]

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Project description:Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. Additionally, ADA-OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA-OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. We then show ADA-OE improves tumor infiltration and clearance by α-HER2 CD4 and CD8 CAR-T with an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.

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Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function [RNA-seq]

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Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function

Project description:This SuperSeries is composed of the SubSeries listed below.

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Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function.

Project description:Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we investigated whether it is possible to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism whereby cancer cells suppress T-cell function by generating a metabolically unfavorable tumor microenvironment (TME). In an in silico screen, we identified ADA and PDK1 as metabolic regulators. We then showed that overexpression (OE) of these genes enhanced the cytolysis of CD19-specific chimeric antigen receptor (CAR) T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampened this effect. ADA-OE in CAR T cells improved cancer cytolysis under high concentrations of adenosine, the ADA substrate, and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics analysis of these CAR T cells revealed alterations of global gene expression and metabolic signatures in both ADA- and PDK1-engineered CAR T cells. Functional and immunologic analyses demonstrated that ADA-OE increased proliferation and decreased exhaustion in CD19-specific and HER2-specific CAR T cells. ADA-OE improved tumor infiltration and clearance by HER2-specific CAR T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR T cells and reveal potential targets for improving CAR T-cell therapy.

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