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Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity

ABSTRACT: Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity

PROVIDER: PRJNA602006 | ENA |

REPOSITORIES: ENA

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Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity

Project description:Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2–induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1. While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21–induced metabolism but caused major transcriptomic changes, including the suppression of IL-21–induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.

2020-02-13 | GSE143903 | GEO

Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity.

Project description: Not available

| S-EPMC7084161 | biostudies-literature

Comparison of RNA expression between Drosophila Lactate Dehydrogenase mutants and controls

Project description:We analyzed RNA levels in Drosophila Lactate Dehydrogenase mutants and precise excision controls during mid-L2 development.

2019-09-01 | GSE119334 | GEO

Quinone-dependent D-lactate dehydrogenase Dld (Cg1027) is essential for growth of Corynebacterium glutamicum on D-lactate

Project description:Corynebacterium glutamicum is able to grow with lactate as sole or combined carbon and energy source. Quinone-dependent L-lactate dehydrogenase LldD is known to be essential for utilization of L-lactate by C. glutamicum. D-lactate also serves as sole carbon source for C. glutamicum ATCC 13032. Here, the gene cg1027 was shown to encode the quinone-dependent D-lactate dehydrogenase (Dld) by enzymatic analysis of the protein purified from recombinant E. coli. The absorption spectrum of purified Dld indicated the presence of FAD as bound cofactor. Inactivation of dld resulted in the loss of the ability to grow with D-lactate, which could be restored by plasmid-borne expression of dld. Heterologous expression of dld from C. glutamicum ATCC 13032 in C. efficiens enabled this species to grow with D-lactate as sole carbon source. Homologs of dld of C. glutamicum ATCC 13032 are not encoded in the sequenced genomes of other corynebacteria and mycobacteria. However, the dld locus of C. glutamicum ATCC 13032 shares 2367 bp of 2372 bp identical nucleotides with the dld locus of Propionibacterium freudenreichii subsp. shermanii, a bacterium used in Swiss-type cheese making. Both loci are flanked by insertion sequences of the same family suggesting a possible event of horizontal gene transfer.

2010-12-02 | GSE25704 | GEO

Transcriptomic analysis of lactate dehydrogenase negative mutant of Enterococcus faecalis V583

Project description:In order to study the effect of lactate dehydrogenase (?ldh 1.2) mutant on the transcriptome DNA microarray technology was used. Stains were grown in a chemically defined medium (CDM-LAB) containing 1.1% of glucose as a carbon sources at 37?C on anaerobic condition to an optical density of 0.6.

2010-12-13 | E-MTAB-472 | biostudies-arrayexpress

Comparison of RNA expression between Drosophila Lactate Dehydrogenase mutants and controls

Project description:Comparison of RNA expression between Drosophila Lactate Dehydrogenase mutants and controls

| PRJNA488802 | ENA

Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin

Project description:Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin

| PRJNA438922 | ENA

The transcription factor Myb enhances CD8+ T cell stemness and antitumor immunity

Project description:The transcription factor Myb enhances CD8+ T cell stemness and antitumor immunity

| PRJNA439010 | ENA

Lactate dehydrogenase: a marker of diminished antitumor immunity.

Project description: Not available

| S-EPMC7051189 | biostudies-literature

Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase

Project description:<p>Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.</p>

2023-08-07 | MTBLS7237 | MetaboLights

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