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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

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.

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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.

2020-04-15 | GSE148669 | GEO

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

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

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Recurrent aneuploidy patterns enable fitness gains in tumor metabolism

Project description:Recurrent aneuploidy patterns enable fitness gains in tumor metabolism

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Multimodal stimulation screens reveal unique and shared regulators limiting T-cell fitness [Icam1]

Project description:It has not been systematically studied whether T-cell fitness regulators uniquely or broadly contribute to specific traits limiting antitumor activity. We performed genome-scale CRISPR/Cas9 knockout screens in primary CD8 T-cells to uncover genes negatively impacting on their fitness upon three modes of stimulation: (1) intense stimulation, causing activation-induced cell death (AICD); (2) acute stimulation, triggering T-cell expansion; (3) chronic stimulation, resulting in dysfunction. Besides established regulators, we uncovered several genes controlling T-cell fitness either specifically or commonly under various stimulation modalities. Ablation of Dap5, 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. Finally, inactivation of Ctbp1 induced T-cell persistence exclusively upon chronic stimulation. Our results functionally annotate T-cell fitness regulators based on their unique or shared contribution to traits limiting T-cell antitumor activity.

2024-02-15 | GSE235710 | GEO