Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tumor-associated Tregs obstruct anti-tumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells

ABSTRACT: We investigated how accumulation of Tregs contributes to T cell dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells. Resected melanoma atissues from tumor-bearing mice were analyzed. The clonal diversity of tumor-associated CD8+ T cells were evaluated by single-cell TCR sequencing respectively, at early or advanced tumor stages or under Treg depletion conditions. TCR-sequencing revealed a clonal shrinkage of tumor-infiltrating CD8+ T cells as tumor progressed, which was associated with reduced survival profile concomitant to increasing Treg proportions.

ORGANISM(S): Mus musculus

PROVIDER: GSE200515 | GEO | 2022/06/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

TCR repertoire analysis by Next-generation sequencing of mouse CD8+ T cells in spleen or tumor

Project description:We have reported that intra-tumoral treatment with 1V270, a phospholipid-conjugated TLR7 agonist,induces local expansion an systemic dispersion of oligoclonal tumor-specific T cells by TCR repertoire analysis using next generation RNAseq methodology. Here, we examined whether systemic 1V270 therapy also induced oligoclonal expansion of tumor-specific T cells. Two groups of BALB/c mice (n=4/group) were i.p. treated with 1V270,a phospholipid-conjugated TLR7 agonist. One cohort of mice was i.v. injected with 4T1-GLF cells (2×104) on day 0. Another cohort did not receive i.v. tumor injection (no tumor-exposed mice). 4T1 cells were orthotopically inoculated on day 21. To examine clonal specificity of tumor-specific T cells, CD8+ cells were isolated from the spleens and the tumor infiltrating lymphocytes of secondarily challenged tumors after initial 1V270 therapy. The TCR repertoires were assessed by next generation RNA sequencing of both TCRαand TCR β genes.

2018-07-31 | E-MTAB-6566 | biostudies-arrayexpress

Tumor-associated Tregs obstruct anti-tumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells

Project description:Tumor-associated Tregs obstruct anti-tumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells

| PRJNA824860 | ENA

Graded Foxo1 Activity in Tregs Differentiates Tumor Immunity from Spontaenous Autoimmunity

Project description:Regulatory T cells (Tregs) expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance1-5; yet, excessive Treg activities suppress anti-tumor immune responses6-8. Compared to resting phenotype Tregs (rTregs) in the secondary lymphoid organs, Tregs in non-lymphoid tissues including solid tumors exhibit an activated Treg (aTreg) phenotype9-11. However, aTreg function and whether its generation can be manipulated to promote tumor immunity without evoking autoimmunity are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg suppression of lymphoproliferative diseases12,13, has an unexpected function in inhibiting aTreg-mediated immune tolerance. We found that aTregs turned over at a slower rate than rTregs, but were not locally maintained in tissues. Transcriptome analysis revealed that aTreg differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic Foxo1 localization, and enhanced Foxo1 phosphorylation at sites of the Akt kinase. Treg-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg homing to non-lymphoid organs, causing CD8+ T cell-mediated autoimmune diseases. Compared to Tregs from healthy tissues, tumor-infiltrating Tregs downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumor-associated Tregs, activate effector CD8+ T cells, and inhibit tumor growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTregs that have a crucial function in suppressing CD8+ T cell responses; and the Foxo signaling pathway in Tregs can be titrated to preferentially break tumor immune tolerance.

2015-11-15 | GSE74957 | GEO

Systematic lineage tracing reveals clonal progenitors and long-term persistence of1 tumor-specific T cells during immune checkpoint blockade

Project description:Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from 3 patients with lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells were enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, revealed that TFH and tumor-specific exhausted CD8+ T cells could be clonally linked to TCF7+ SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones revealed persistence in the peripheral blood for years after ICB therapy.

2023-02-14 | GSE186446 | GEO

Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

2023-02-13 | GSE185206 | GEO

Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scTCR-seq]

2023-02-14 | GSE185205 | GEO

Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scRNA-seq]

2023-02-14 | GSE185204 | GEO

Clonal replacement of tumor-specific T cells following PD-1 blockade [single cells]

Project description:Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, the clonal origin of tumor-specific T cells following checkpoint blockade in patients remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)- sequencing on site-matched tumors from patients with basal cell carcinoma (BCC) pre- and post-anti-PD-1 therapy. Tracking TCR clonotypes and transcriptome phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the response to treatment was accompanied by a clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this response was not accompanied by an expansion of pre-existing tumor-specific T cell clonotypes; rather, expanded T cell clones post-therapy comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in tumor-specific exhausted CD8+ T cells, compared to other distinct T cell phenotypes, and was more evident in patients who exhibited a clinical response to treatment. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that the chronic activation of pre-existing tumor-infiltrating T cells may limit their re-invigoration following checkpoint blockade, and that a successful response relies on the expansion of a distinct repertoire of tumor-specific T cell clones.

2019-05-24 | GSE123813 | GEO

Clonal replacement of tumor-specific T cells following PD-1 blockade [bulk RNA]

2019-05-24 | GSE123812 | GEO

Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth

Project description:Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-HSD1 (encoded by Hsd11b1). Here we find that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth but reduced in vivo tumor progression, which corresponded with increased frequencies of tumor-infiltrating CD8+ T cells (TIL) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of Tconv activation in tumor-infiltrating Treg. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11β-HSD1 reduced tumor growth to the same degree as gene knockout, and rendered immunotherapy-resistant tumors susceptible to PD-1 blockade. Given that HSD11B1 expression is upregulated in many human tumors and that inhibition of 11β-HSD1 is well-tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy.

2023-09-20 | GSE231303 | 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