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Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and tumor killing

ABSTRACT: Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and tumor killing

PROVIDER: PRJNA971744 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24518590_1.fastq.gz	Fastqsanger.gz
	SRR24518590_2.fastq.gz	Fastqsanger.gz
	SRR24518591_1.fastq.gz	Fastqsanger.gz
	SRR24518591_2.fastq.gz	Fastqsanger.gz
	SRR24518592_1.fastq.gz	Fastqsanger.gz

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Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity

Project description:The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is highly amenable to perturbation by the tumor microenvironment. It is therefore of tremendous interest to bypass immunosuppressive signaling in the tumor microenvironment and to identify factors that augment T cell immunometabolism, cytotoxic effector functions and eventually tumor killing. Whether ionic signals serve as aberrant immune signals and influence the adaptive human antitumor immune response is still largely unexplored. We demonstrate a significant enrichment of sodium in solid tumors of breast cancer patients, which leaves a transcriptomic imprint on intratumoral immune cells. Sodium chloride (NaCl) enhanced the activation state and effector functions of human CD8+ memory T cells. These functional alterations were associated with improved metabolic fitness, in particular with an increase in glycolysis and oxidative phosphorylation and overall nutrient uptake. These NaCl-induced effects translated into increased tumor cell killing in vitro and in a tumor mouse model in vivo. We therefore propose NaCl as a positive regulator of acute antitumor immunity, which could be harnessed for ex vivo conditioning of adoptively transferred T cells in the future.

2024-06-21 | GSE232149 | GEO

Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity

Project description:Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity

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Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and tumor killing

Project description:To gain mechanistic insight into the effect of NaCl on CD8+ T cells, we explored the specific impact of NaCl on the bulk transcriptome of human memory CD8+ T cells.

2024-06-21 | GSE232365 | GEO

single cell-RNA sequencing for glioma cells and immune cells from mouse brain tumor following propionate supplementation

Project description:To identify the effect of propionate on brain tumor microenvironment, we isolated immune cells and brain tumor cells of brain from mice supplemented with sodium chloride as control or sodium propionate in drinking water

2025-04-23 | GSE233411 | GEO

Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.

Project description:The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8+ T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8+ T cells are linked to sodium-induced upregulation of Na+/K+-ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells.

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Genomic and functional characterization of the tumor-killing capacity of Imiquimod-activated plasmacytoid dendritic cells

Project description:Plasmacytoid dendritic cells (pDCs) are a subset of DCs that act as important modulators of anti-tumor immune responses. pDCs have been associated with poor prognosis of tumor patients. Despite this, upon TLR7 activation, pDCs have also been shown to acquire tumor killing capacities, and we previously provided evidence on the role of activated pDCs in eliminating tumor cells in vivo, independently of adaptive immunity. In this study we investigated the mechanism by which pDCs acquire tumor-killing capacities following TLR7/8 triggering by Imiquimod (IMQ). By combining pathway perturbation and analysis of transcriptome, surfaceome, secretome, and killing function, we identified the MAPKs and NF-kB pathways as important downstream mediators of the tumor-killing ability of these cells. JNK inhibition reduces killing by secreted factors whereas p38 or NF-kB inhibition enhances cell mediated killing. Analysis of surface and secreted proteins revealed differential control of expression and secretion by IFN-I/-II, MAPK and NF-kB, while indicating that a complex signaling network is necessary to shape the cytotoxic phenotype of activated pDCs. Our integrated analysis converged on a new pDCs killing gene signature that is predictive of survival in cohorts of melanoma patients. These newly identified markers will be instructive for the rationale design and interpretation of further single-cell and functional approaches aimed at studying the role of pDCs in the tumor microenvironment. These might pinpoint novel strategies to improve cancer management and treatment, by modulating the pDCs pro- vs anti-tumorigenic functions.

2025-05-28 | GSE255537 | GEO

MULTIMODAL STIMULATION SCREENS REVEAL UNIQUE AND SHARED GENES LIMITING T-CELL FITNESS

Project description:T-cell dysfunction genes limit antitumor activity and may serve as therapeutic targets. It has not been systematically studied whether there are regulators that either uniquely or broadly contribute to T-cell fitness. We performed genome-scale CRISPR/Cas9 knockout screens in primary CD8 T-cells to uncover genes negatively impacting on fitness upon three modes of stimulation: (1) intense stimulation, triggering activation-induced cell death (AICD); (2) acute stimulation, triggering T-cell expansion; (3) chronic stimulation, causing dysfunction. Besides established regulators, we uncovered genes controlling T-cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increased translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T-cell clustering amplified T-cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induced functional T-cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T-cell antitumor activity.

2024-02-16 | PXD043545 | Pride

Sodium chloride generates anti-inflammatory Th17 cell responses but amplifies Th17 cell pathogenicity in pro-inflammatory cytokine microenvironments

Project description:T helper cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here we demonstrate that high NaCl conditions induced a stable, pathogen-specific, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17-expression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a pro-inflammatory and TGF--low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

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ITPK1 sensitizes tumor cells to IgA-dependent neutrophil killing in vivo

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Recurrent aneuploidy patterns enable fitness gains in tumor metabolism

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