Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Palmitate suppresses CD8+ T cell antitumoral response by disrupting mitochondrial metabolism [RNA-seq]

ABSTRACT: Accumulation of lipids in the tumor microenvironment (TME) is a feature of several solid tumors and increased palmitate (PA) availability fosters tumor progression and metastases. The intrinsic effects of PA on cancer cells are well understood, but its role in modulating CD8+ T cells (CTL) functional performances remains elusive. Here, we found that PA alters the mitochondrial metabolism of CTL and prevents their effector functions in an irreversible manner, resulting in impaired antitumoral immunity. Mechanistically, PA-induced mitochondrial blocking demotes histone acetylation and chromatin accessibility and decreases the transcription of genes promoting DNA replication and production of effector molecule production. We identified the metabolic enzyme Sphingosine Kinase 2 (SPHK2) as a molecular target of PA in establishing CTL dysfunction. Consistently, pharmacological inhibition of SPHK2 restored CTL mitochondrial fitness, effector functions and anti-tumor potential. Thus, we reveal that PA fosters tumor progression by impairing CTL antitumor immunity and highlight the therapeutic potential of inhibiting SPHK2 activity to optimize T cellfunctionality.

ORGANISM(S): Mus musculus

PROVIDER: GSE251815 | GEO | 2025/10/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Palmitate suppresses CD8+ T cell antitumoral response by disrupting mitochondrial metabolism [ATAC-seq]

Project description:Accumulation of lipids in the tumor microenvironment (TME) is a feature of several solid tumors and increased palmitate (PA) availability fosters tumor progression and metastases. The intrinsic effects of PA on cancer cells are well understood, but its role in modulating CD8+ T cells (CTL) functional performances remains elusive. Here, we found that PA alters the mitochondrial metabolism of CTL and prevents their effector functions in an irreversible manner, resulting in impaired antitumoral immunity. Mechanistically, PA-induced mitochondrial blocking demotes histone acetylation and chromatin accessibility and decreases the transcription of genes promoting DNA replication and production of effector molecule production. We identified the metabolic enzyme Sphingosine Kinase 2 (SPHK2) as a molecular target of PA in establishing CTL dysfunction. Consistently, pharmacological inhibition of SPHK2 restored CTL mitochondrial fitness, effector functions and anti-tumor potential. Thus, we reveal that PA fosters tumor progression by impairing CTL antitumor immunity and highlight the therapeutic potential of inhibiting SPHK2 activity to optimize T cellfunctionality.

2025-10-06 | GSE251812 | GEO

Sphingosine kinase 2 signaling modulates altered expression profile of host genome in a murine model of Pseudomonas aeruginosa pneumonia.

Project description:We present the set of pseudomonas responsive genes activated in the WT mice in comparison with Sphk2-/- thereby revealing the genes that could contribute to the protection seen in Sphk2-/- mice. Methods: Lung mRNA profiles of 8 week old male wild-type (WT) and Sphingosine kinase 2 knock out (Sphk2−/−) mice were generated by deep sequencing, in triplicate, using Illumina GAIIx. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two way ANOVA (ANOVA). qRT–PCR validation was performed using SYBR Green assays Genetic deletion of Sphk2-/-resisted alteration of host pulmonary genome by PA infection of the lungs promoting its own virulence thereby conferring significant protection against PA pneumonia.

2019-01-01 | GSE121359 | GEO

Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

Project description:Tumor-associated macrophages (TAMs) dynamically influence anti-tumor immunity. Understanding TAM function and plasticity is therefore critical to design immunotherapies. By combining syngeneic models of colorectal and pancreatic cancer with cell type-specific deletion of Zeb1, a key driver of epithelial-to-mesenchymal transition that is expressed in subsets of TAMs, we discovered that ZEB1 is an intrinsic regulator of TAM-controlled T cell trafficking. ZEB1 supports secretion of a subset of chemokines via the constitutive pathway, including CCL2 and CCL22, by promoting their biosynthesis, vesicular transport and release. This elevates CCL2 and CCL22-driven cytotoxic T cell (CTL) recruitment in vitro and fosters immunosurveillance by CTLs in tumors and metastases as well in an organotypic model for adoptive cell transfer. Our study identifies ZEB1 in TAMs as a facilitator of anti-tumor immunity, suggests a window of opportunity for cytokine-guided CTL tropism and reinforces the importance of onco-immunological context, particularly in the design of macrophage-/ cytokine-depleting strategies.

2025-05-07 | GSE286348 | GEO

Hypoxia-inducible factors enhance CD8+ T cell effector responses to persistent antigen.

Project description:Cytolytic activity by CD8+ cytotoxic T lymphocytes (CTL) is a powerful tactic in the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTL is progressively dampened during chronic infection - yet the environmental cues and molecular pathways controlling immune “exhaustion” remain unclear. We find CTL immunity is regulated by the central transcriptional response to hypoxia, mediated by the von-Hippel-Lindau/Hypoxia-Inducible-Factor (VHL/HIF) pathway. Deletion of VHL, the primary negative regulator of HIF, leads to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTL display enhanced control of persistent viral infection and neoplastic growth. We find HIF and oxygen influence expression of pivotal CTL transcription, effector and costimulatory-inhibitory molecules, which is relevant to strategies to promote viral and tumor clearance.

2013-09-29 | GSE50158 | GEO

CXCR6 Positions Cytotoxic T Cells to Receive Critical Survival Signals in the Tumor Microenvironment

Project description:Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew, but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTL involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTL in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DC) expressing the CXCR6 ligand CXCL16. CCR7+ DC also express and trans-present the survival cytokine IL-15. CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTL in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.

2021-06-30 | GSE179111 | GEO

Doxycycline treated cytotoxic T lymphocytes

Project description:Recent work in immunometabolism has emphasised the role of mitochondria in both the innate and adaptive immune system. Mitochondria are important in T cell development and differentiation, but less is known about their role in CD8+ effector T cells (CTLs). We found that CTLs that lack the mitochondrial deubiquitinase USP30 undergo promiscuous mitophagy, destroying most of the cellular mitochondria. Surprisingly, this results in a markedly diminished killing capacity, while motility, signalling and secretion remain intact. This study uses quantitative DIA proteomics to measure the impact of USP30 deficiency on the global proteome of IL-2 maintained, 4.5 h TCR retriggered and 4.5 h TCR retriggered + cycloheximide CTL. We also measured the impact of pharmacologically inhibiting mitochondrial translation by performing Quantitative DIA proteomics on IL2 maintained or TCR retriggered CTL treated with the mitochondrial translation inhibitor doxycycline for 4.5 hrs. Unexpectedly, inhibition of mitochondrial translation, through genetic or pharmacologic methods, was the mechanism by which CTL killing was impaired. Reduced mitochondrial translation triggered attenuated cytosolic translation which precluded replenishment of secreted effector molecules thereby limiting the capacity of CTLs to serially kill multiple targets. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.

2022-06-09 | PXD026948 | Pride

Transcription profiling of mouse control cell line and a cell line surviving exposure to tumor-specific CTL (cytolytic T lymphocyte)

Project description:The CMS4 sarcoma, kindly provided by A. DeLeo (University of Pittsburgh, Pittsburgh, PA), is a solid tumor of BALB/c (H-2d) origin, which grows aggressively in naive, syngeneic hosts following a s.c. transplant. Although the parental tumor cell line forms few metastatic foci in the lungs following i.v. administration, a highly metastatic subline, termed CMS4-met, was established from lung digests of those mice as described (Ryan MH, Bristol JA, McDuffie E, Abrams SI. Regression of extensive pulmonary metastases in mice by adoptive transfer of antigen-specific CD8(+) CTL reactive against tumor cells expressing a naturally occurring rejection epitope. J Immunol 2001;167:4286-92).<br>In this experiment we compare the gene expression profiles between a control cell line and a cell line surviving exposure to tumor-specific CTL (cytolytic T lymphocyte). CMS4-met cells were injected iv. to the mouse tails. Three days later, either saline or tumor-specific CTL were injected iv into mouse tails. Single cell suspensions were made from mouse lungs and put in culture. Tumor cells were recovered from cultures. Tumor cells established from mice receiving saline were termed CMS4-met.cntl. Tumor cells established from mice receiving CTL were termed CMS4-met.sel. The gene expression profiles of these two tumor cell lines were then compared to CMS4-met.

2005-05-08 | E-MEXP-287 | biostudies-arrayexpress

Proteome of WT and Usp30KO cytotoxic T lymphocytes

Project description:Recent work in immunometabolism has emphasised the role of mitochondria in both the innate and adaptive immune system. Mitochondria are important in T cell development and differentiation, but less is known about their role in CD8+ effector T cells (CTLs). We found that CTLs that lack the mitochondrial deubiquitinase USP30 undergo promiscuous mitophagy, destroying most of the cellular mitochondria. Surprisingly, this results in a markedly diminished killing capacity, while motility, signalling and secretion remain intact. This study uses quantitative DIA proteomics to measure the impact of USP30 deficiency on the global proteome of IL-2 maintained, 4.5 h TCR retriggered and 4.5 h TCR retriggered + cycloheximide CTL. Unexpectedly, inhibition of mitochondrial translation, through genetic or pharmacologic methods, was the mechanism by which CTL killing was impaired. Reduced mitochondrial translation triggered attenuated cytosolic translation which precluded replenishment of secreted effector molecules thereby limiting the capacity of CTLs to serially kill multiple targets. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.

2022-06-09 | PXD021508 | Pride

Palmitate suppresses CD8+ T cell antitumoral response by disrupting mitochondrial metabolism

Project description:Palmitate suppresses CD8+ T cell antitumoral response by disrupting mitochondrial metabolism

| PRJNA1055486 | ENA

scRNA-seq analyses on Thy1.1+Thy1.2+ MDR1-sufficient and Thy1.1+Thy1.2- MDR1-deficient P14 CD8+ T cells from ten congenically-transferred and LCMV-infected wild type B6 mice at day 8 post-infection

Project description:Multidrug resistance (MDR)-1 acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiologic functions remain enigmatic. Using a recently-developed MDR1-knockin reporter allele (Abcb1aAME/+), we found that constitutive MDR1 expression amongst hematopoietic cells was observed mainly in cytolytic lymphocytes—including CD8+ cytotoxic T lymphocytes (CTL) and natural killer cells—and regulated by Runt-related (Runx) transcription factors. Although MDR1 was dispensable for naïve CD8+ T cell development, it was required for both normal accumulation of effector CTL following acute viral infection and protective function of memory CTL upon challenge with an intracellular bacterium. MDR1 acted early after naïve CD8+ T cell activation to suppress oxidative stress, enforce survival and safeguard mitochondrial function in developing CTL. Together, these data highlight an important endogenous function of MDR1 in cell-mediated immune responses, and suggest that ongoing efforts to intentionally inhibit MDR1 in cancer patients could be counter-productive.

2020-02-28 | GSE143140 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data