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Ex vivo activation of the GCN2 pathway metabolically reprograms T cells leading to enhanced adoptive cell therapy

ABSTRACT: Ex vivo activation of the GCN2 pathway metabolically reprograms T cells leading to enhanced adoptive cell therapy

PROVIDER: PRJNA1074242 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27899677.fastq.gz	Fastqsanger.gz
	SRR27899678.fastq.gz	Fastqsanger.gz
	SRR27899679.fastq.gz	Fastqsanger.gz
	SRR27899680.fastq.gz	Fastqsanger.gz
	SRR27899681.fastq.gz	Fastqsanger.gz

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Ex vivo activation of the GCN2 pathway metabolically reprograms T cells leading to enhanced adoptive cell therapy

Project description:The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the General Control Non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Further characterization revealed that halo-treated CD8+ T cells increased expression of the large neutral amino acid (LNAA) transporter CD98 as well as the co-stimulatory marker 4-1BB. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into mice bearing well-established tumors led to robust tumor control and curative responses. Halo-treated T cells also synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halofuginone can enhance T cell metabolism, effector function and anti-tumor activity, with the potential to augment existing clinical immunotherapeutic approaches.

2024-02-17 | GSE255244 | GEO

Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.

Project description:The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.

| S-EPMC10983112 | biostudies-literature

Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Project description:Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

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Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

Project description:Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

| PRJNA1139138 | ENA

Eukaryotic Ribosome GCN2 interaction Hydrogen/Deuterium Exchange Mass Spectrometry

Project description:General control nonderepressible 2 (GCN2) phosphorylates eIF2α, regulating translation in response to nutritional stress. Here, we show that mammalian ribosomes are potent GCN2 activators. Hydrogen/deuterium exchange–mass spectrometry (HDX-MS) showed GCN2 interacting with domain II of the uL10 P-stalk protein. The P-stalk is a uL10/P12/P22 pentameric complex that is part of the ribosomal GTPase-associated center. Recombinant human P-stalk greatly stimulates GCN2. Both domain II of uL10 and the C-terminal tails of P1 and P2 are necessary for maximal GCN2 activation. On actively translating ribosomes, the C-terminal tails of P1 and P2 are sequestered by elongation factors, suggesting P-stalk availability could link translational stress to GCN2 activation.

2019-05-24 | PXD013051 | Pride

Schistosoma mansoni infection metabolically reprograms the myeloid lineage in a mouse model of metabolic disease

Project description:Schistosoma mansoni infection metabolically reprograms the myeloid lineage in a mouse model of metabolic disease

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Selective control of metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae

Project description:When eukaryotic cells are deprived of amino acids, uncharged tRNAs accumulate and activate the conserved GCN2 protein kinase. We examine how yeast growth and tRNA charging or aminoacylation is affected during amino acid depletion in the presence and absence of GCN2. tRNA charging is measured using a microarray technique which allows for simultaneous measurement of all cytosolic tRNAs. A fully prototrophic and its isogenic GCN2 deletion strain were used. We measured relative tRNA charging levels in yeast strains with an intact and deleted GCN2.

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GCN2 Adapts Protein Synthesis to Scavenging-Dependent Growth

Project description:Compared protein synthesis in Gcn2 WT vs Gcn2 KO murine PDAC cells (KRPC) in amino acid-replete or leucine-free media.

2022-10-13 | PXD028143 | Pride

ISR pathway activation signatures in MEFs: GCN2 and PERK

Project description:In response to different cellular stressors, the ISR kinases, PERK, PKR, HRI and GCN2, activate downstream transcriptional programs. While the core ISR transcription program is well characterized, markers that are specific to each individual ISR kinase activation pathway are not known. To identify markers that are induced by PERK or GCN2, but not the other ISR kinases, we subjected WT, GCN2-/-, and PERK-/- MEFs to amino acid starvation (RPMI 1640 SILAC -Lys -Arg) or Thapsigargin (200nM) treatment for 6 hours to activate the GCN2 and PERK pathways, respectively and performed RNA sequencing.

2022-07-01 | GSE179559 | GEO

Global Phosphoproteomics Pinpoints Uncharted Gcn2-Mediated Modes of Translational Control

Project description:To identify new Gcn2 target proteins, we performed a set of Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based quantitative phosphoproteomics experiments, in which we compared WT cells to gcn2∆ and sui2S52A cells (n=3), all treated, or not, with rapamycin, which has previously been shown to stimulate eIF2alpha phosphorylation by Gcn2.

2021-03-22 | PXD021109 | Pride

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