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MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

ABSTRACT: MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

PROVIDER: PRJNA1245427 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32960446_1.fastq.gz	Fastqsanger.gz
	SRR32960446_2.fastq.gz	Fastqsanger.gz
	SRR32960447_1.fastq.gz	Fastqsanger.gz
	SRR32960447_2.fastq.gz	Fastqsanger.gz
	SRR32960448_1.fastq.gz	Fastqsanger.gz

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MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

Project description:Loss of mitochondrial function contributes to CD8+ T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEKi uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEKi during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEKi reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEKi in enhancing immunotherapy efficacy.

2025-04-02 | GSE293649 | GEO

Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

Project description:The failure of T-cells to control tumor growth has been associated with several functional defects that collectively lead to T-cell “exhaustion.” This phenotype results from chronic antigen stimulation within the tumor microenvironment, but how repetitive antigenic stimulation leads to T-cell exhaustion remains poorly defined. Here we show that persistent antigen stimulation induces mitochondrial oxidative stress that reduces tricarboxylic acid (TCA) cycle activity. The resultant bioenergetic compromise impairs nucleotide triphosphate synthesis, induces endoplasmic reticulum (ER) stress, and activates an exhaustion-associated gene expression program. Reversal of oxidative stress with N-acetylcysteine effectively restores T-cell proliferation, effector function, and memory-associated gene expression and enhances anti-tumor T-cell efficacy in vivo. These data reveal that induction of mitochondrial oxidative stress is a critical component of terminal T-cell dysfunction. Furthermore, treatments that restore mitochondrial redox are sufficient to prevent T-cell exhaustion and enhance anti-tumor immunity.

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Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

Project description:Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

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Neonatal CD8+ T cells resist terminal exhaustion during chronic infection

Project description:Neonatal CD8+ T cells resist terminal exhaustion during chronic infection

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ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion

Project description:CD8+ T cell exhaustion limits the immune response to tumors because of ineffective T cell effector functions. Thus, therapies that inhibit T-cell exhaustion are critical for optimizing cancer treatment. Recent studies have implicated epigenetic proteins in T-cell exhaustion. Here, we identified activating transcription factor 7 interacting protein (ATF7ip) as an epigenetic protein critical for inducing T cell exhaustion. Loss of Atf7ip in CD8+ T cells results in decreased terminal exhaustion and increased numbers of progenitor-exhausted cells in both chronic viral infections and cancer. Owing to decreased exhaustion, Atf7ip-deficiency in CD8+ T cells leads to an enhanced immune response to tumors. Mechanistically, ATF7ip functions to stimulate the deposition of repressive H3K9me3 at critical immune-effector gene loci, such as Il7r and Il2 leading to enhanced exhaustion. Our data suggest that ATF7ip may be a rational target for deletion in adoptive T-cell therapies to reduce CD8+ T-cell exhaustion.

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ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion III

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ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion II

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All -trans retinoic acid suppresses CD8+ T cell terminal exhaustion which enhances anti–PD-1 efficacy against glioblastoma [RNA-Seq]

Project description:Terminal exhaustion of CD8⁺ T cells limits the efficacy of immune checkpoint blockade (ICB), particularly in glioblastoma, which is characterized by an immunosuppressive tumor microenvironment. Therefore, better understanding of the regulators of terminal exhaustion could overcome intrinsic resistance to ICB and thereby improve the efficacy of immunotherapy. In this study, we find that all-trans retinoic acid (ATRA) suppresses CD8⁺ T cell terminal exhaustion. Administration of ATRA during CD8⁺ T cell activation in vitro conferred resistance to terminal exhaustion and preserved effector cytokine production and effector function. Mechanistically, ATRA selectively induced the expression of the long isoform of T cell factor 1 (TCF-1βBD), through activation of the canonical WNT/β-catenin pathway. In a mouse glioma model, adoptively transferred ATRA-conditioned CD8⁺ T cells exhibited exhaustion resistance, which led to superior tumor-infiltrating CD8+ T cell polyfunctionality and enhanced glioma suppression. Oral administration of ATRA also suppressed terminal exhaustion of tumor-infiltrating CD8+ T cells and synergized with anti-PD-1 therapy, overcoming resistance in mouse models of glioma. Synergistic ATRA administration and anti-PD-1 treatment displayed significant therapeutic potential in mouse recurrent glioma model. Single-cell transcriptomic analysis of glioblastoma patients receiving anti-PD-1 therapy revealed that CD8⁺ T cells from responders were enriched for retinoic acid responsive and WNT-associated gene signatures, which correlated with improved survival. These findings establish ATRA as a modulator of CD8⁺ T cell exhaustion by inducing WNT/β-catenin dependent TCF-1βBD expression. This pathway offers therapeutic potential to overcome resistance to ICB in glioma.

2026-05-21 | GSE320177 | GEO

Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day30]

Project description:Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day30]

| PRJNA980734 | ENA

Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day8]

Project description:Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day8]

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