Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A distinct gene module uncouples dysfunction from activation in tumor-infiltrating T cells (batch 4)

ABSTRACT: Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact.

ORGANISM(S): Mus musculus

PROVIDER: GSE86031 | GEO | 2016/09/07

SECONDARY ACCESSION(S): PRJNA340026

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A distinct gene module uncouples dysfunction from activation in tumor-infiltrating T cells (batch 2)

Project description:Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact.

2016-09-07 | GSE86039 | GEO

A distinct gene module uncouples dysfunction from activation in tumor-infiltrating T cells (batch 3)

2016-09-07 | GSE86030 | GEO

A distinct gene module uncouples dysfunction from activation in tumor-infiltrating T cells (batch 1)

2016-09-07 | GSE86028 | GEO

A distinct gene module uncouples dysfunction from activation in tumor-infiltrating T cells (part 2)

2016-09-07 | GSE85954 | GEO

A distinct gene module uncouples dysfunction from activation in tumor-infiltrating T cells (part 1)

2016-09-07 | GSE85951 | GEO

Expression data for CD8 TILs subpopulations sorted by Tim3 and PD1

2016-09-07 | GSE85947 | GEO

Endogenous glucocorticoid signaling regulates effector differentiation and development of dysfunction in CD8+ T cells in the tumor microenvironment

Project description:Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naive to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs resulted in improved effector differentiation, reduced TCF-1 expression, and failure to develop dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of several dysfunction-associated genes upon T cell activation. In the TME, monocyte/macrophages produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well localized pharmacologic inhibition of glucocorticoid biosynthesis dramatically improved tumor growth control. Active glucocorticoid signaling further associated with failure to respond to checkpoint blockade in both pre-clinical models and melanoma patients, highlighting the clinical relevance of targeting endogenous steroid signaling to enhance anti-tumor T cell responses.

2020-07-01 | GSE153556 | GEO

Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

Project description:T cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction in cancer. We identify that CD36 limits anti-tumor CD8+ T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+ TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally ‘exhausted’ CD8+ TILs increased CD36 expression and CD36-deficient CD8+ TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL), induces lipid peroxidation in CD8+ TILs, and enhances p38 kinase phosphorylation. Moreover, we found that OxLDL inhibits CD8+ T cell functions in a CD36/p38-dependent manner. Furthermore, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+ TILs. These results define a key role for an oxidized lipid-CD36-p38 axis in promoting intratumoral CD8+ T cell dysfunction.

2021-03-31 | GSE171194 | GEO

Gene expression of dysfunctional CD8+ T cells from the tumor microenvironment

Project description:Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous anti-tumor response, immune regulatory pathways can subvert the effector phase and enable tumor escape. Negative regulatory pathways include extrinsic suppression mechanisms but also a T cell-intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining dysfunctional TILs, and it is clear that PD-1 alone is not sufficient. Recently, we identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro. In the current study we show that the Egr2-driven cell surface proteins, LAG-3 and 4-1BB, identify dysfunctional tumor antigen-specific CD8+ TIL. Co-expression of 4-1BB and LAG-3 was seen on a majority of CD8+ TIL but not in lymphoid organs. Functional analysis revealed defective IL-2 and TNF-α production yet retained expression of IFN-γ and Treg-recruiting chemokines. Transcriptional and phenotypic characterization revealed co-expression of multiple additional co-stimulatory and co-inhibitory receptors. Administration of anti-LAG-3 plus anti-4-1BB mAbs was therapeutic against tumors in vivo, which correlated with a reversal of TIL dysfunction and restored effector phenotype. Our results indicate that co-expression of LAG-3 and 4-1BB characterize dysfunctional T cells within tumors, and that targeting these receptors has therapeutic utility.

2016-04-05 | GSE79919 | GEO

Transcriptome differences in HCC infiltrated CD8+ T cells in effector and exhaustion state

Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.

2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress

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