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The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

ABSTRACT: The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

PROVIDER: PRJNA655350 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12390683_1.fastq.gz	Fastqsanger.gz
	SRR12390683_2.fastq.gz	Fastqsanger.gz
	SRR12390684_1.fastq.gz	Fastqsanger.gz
	SRR12390684_2.fastq.gz	Fastqsanger.gz
	SRR12390685_1.fastq.gz	Fastqsanger.gz

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The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

Project description:Study aim: Investigate the effect of S-2HG (2-hydroxyglutarate) metabolite on the mRNA levels of human CD8 T cells Methods: Naïve CD8 T cells were isolated from human healthy donors. The CD8 T cells were aCD3/CD28 beads (1:1 bead-to-cell ratio) and IL-2 (30 U/ml) for 4 days. The cells were treated with S-2HG (0.4 mM) or vehicle (H2O) from the day of isolation and for 12 days before collection. Library preparation and paired-end RNA sequencing using Illumina NextSeq 500, as well as downstream data analysis, were performed by Active Motif.

2020-08-05 | GSE155715 | GEO

The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome.

Project description:Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo-generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and persistence, which are necessary features for therapeutic success and prevention of disease relapse. However, memory CAR-T cells are rarely used in the clinic due to generation challenges. We previously reported that mouse CD8 T cells cultured with the S enantiomer of the immunometabolite 2-hydroxyglutarate (S-2HG) exhibit enhanced antitumor activity. Here, we show that clinical-grade human donor CAR-T cells can be generated from naive precursors after culture with S-2HG. S-2HG-treated CAR-T cells establish long-term memory cells in vivo and show superior antitumor responses when compared with CAR-T cells generated with standard clinical protocols. This study provides the basis for a phase 1 clinical trial evaluating the activity of S-2HG-treated CD19-CAR-T cells in patients with B-cell malignancies.

| S-EPMC7509862 | biostudies-literature

2-hydroxyglutarate modulates histone methylation using both RNA/ChIP-seq

Project description:2-hydroxyglutarate (2-HG) is an oncometabolite accumulating in certain cancers and some neurometabolic diseases. In cancers 2-HG accumulation is induced by a gain-of-function mutation in isocitrate dehydrogenase (IDH) genes, leading to conversion of alpha-ketoglutarate (a-KG) into 2-HG

2023-04-15 | E-MTAB-11328 | biostudies-arrayexpress

Knocking out BATF improves CAR-T cell efficacy by resisting exhaustion and forming central memory cells

Project description:Chimeric antigen receptor modified T (CAR-T) cell therapy has limited efficacy against solid tumor, one major challenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypofunction CAR-T cell model, and found that knocking out BATF improved the performance of CAR-T cells. In different types of CAR-T cells and mouse OT-1 cells, knocking out BATF endows T cells with improved resistance to exhaustion and better tumor eradication efficacy. We find that BATF binds to and up-regulates a subset of exhaustion genes in human CAR-T cells. Furthermore, BATF regulates the expression of genes involved in the development of effector and memory cells, and knocking out BATF shifts the population towards more central memory subset. Therefore, we conclude that BATF is a key factor limiting CAR-T cell function, and its depletion improves CAR-T cells efficacy against solid tumor.

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D- 2-hydroxyglutarate is an immunometabolite that accumulates in macrophages after TLR activation and inhibits inflammatory responses

Project description:Macrophages undergo extensive metabolic rewiring upon activation and this serves many roles beyond the production of energy and anabolic building blocks. So-called immunometabolites that accumulate upon immune activation can serve as co-factors for enzymes and can mediate posttranslational modifications of histones, transcription factors, enzymes and other key proteins that modulate macrophage function. As such, the Krebs-cycle-associated metabolites succinate and itaconate emerged as key regulators of macrophages. 2-hydroxyglutarate (2HG) is structurally similar to Krebs-cycle metabolite alpha-ketoglutarate and exists as two enantiomers. D-2HG is well studied as an oncometabolite in cancer cells and more recently, L-2HG received some attention in the immunometabolism field. Here we describe that 2HG levels peak during later stages of LPS-induced inflammatory responses in mouse and human macrophages. Surprisingly, D-2HG was the most abundant enantiomer in macrophages and its LPS-induced accumulation may be explained by the inverse kinetics of D-2HG-degrading D-2HG dehydrogenase (D2HGDH) and the time-dependent induction of Hydroxyacid-Oxoacid Transhydrogenase (HOT), which makes D-2HG as a byproduct. D-2HG kinetics fit transcriptomics and functional data, together indicating that D-2HG suppresses inflammatory responses in macrophages in vitro. D-2HG also regulates local and systemic inflammatory responses in vivo. Finally, we show that D-2HG likely exerts in anti-inflammatory effects on NFkB target genes independently of aKG-dependent dioxygenases. Together, this study unexpectedly classifies D-2HG as an immunometabolite that can inhibit inflammatory macrophage responses.

2022-06-24 | GSE196315 | GEO

Genome wide analysis of gene expression changes upon restoration of L-2-hydroxyglutarate dehydrogenase (L2HGDH)

Project description:Renal cancer cells with basal eleavtion of L-2-hydroxyglutarate were transduced with control vector or cDNA encoding L2HGDH

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Paclitaxel resistance in ovarian cancer increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control

Project description:The microtubule-stabilising drug paclitaxel has activity in relapsed ovarian cancer. However, resistance frequently develops. Oncolytic adenoviruses are a novel cancer therapy, and replicate selectively within and lyse malignant cells, leading to productive infection of neighbouring cells. We found increased efficacy of adenoviruses of multiple subtypes in paclitaxel-resistant ovarian cancer cells. There was increased expression of a key adenovirus receptor, CAR (coxsackie adenovirus receptor), due to increased transcription that resulted from histone modification. Moreover, CAR transcription increased in intraperitoneal xenografts with acquired paclitaxel resistance and in tumours from patients with paclitaxel-resistant ovarian cancer. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer and that inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms. Parental SKOV3 and paclitaxel-resistant SKOV3-TR cells were analysed in duplicate

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Effect of L-2-hydroxyglutarate on gene expression in mice round spermatids

Project description:2-hydroxyglutarate (2HG) is known to function as an epigenetic regulator in cancer and certain transient biological processes. Among all organs in mice, the testis contains the highest baseline physiological levels of 2HG. We found that L-2HG is generated in specific stages of spermatogenesis namely starting from pachytene up to round spermatids.

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TonEBP increases TRIM37

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