Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Altered costimulatory signaling and hypoxia support chromatin landscapes that limit the functional potential of exhausted T cells in cancer [RNA-seq]

ABSTRACT: Increases in terminally exhausted T cells in the tumor are associated with poor responses to immunotherapy, yet the mechanisms that promote progression to terminal exhaustion remain undefined. To understand the effect of epigenetic changes in subsets of tumor-infiltrating CD8+ T cells, we performed RNA-seq to understand changes in gene expression. CD8 T cells were sorted from the murine B16 melanoma tumor using PD1 and Tim3 expression to define four subsets: PD1lo, PD1mid, PD1hi, and PD1hiTim3+. Additional control samples include paired CD44+ cells from the tumor-draining lymph node of tumor bearing mice, and OT-I effector CD8 T cells isolated from Vaccinia-ova infection. CD8 TIL PD1hi Tim3+ from B16 tumors treated with IgG control, anti-PD1 or anti-41BB agonist immunotherapies were also isolated for RNAseq.

ORGANISM(S): Mus musculus

PROVIDER: GSE175408 | GEO | 2022/08/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Altered costimulatory signaling and hypoxia support chromatin landscapes that limit the functional potential of exhausted T cells in cancer [CUT&RUN]

Project description:Increases in terminally exhausted T cells in the tumor are associated with poor responses to immunotherapy, yet the mechanisms that promote progression to terminal exhaustion remain undefined. We profiled the chromatin landscape of subsets of tumor-infiltrating CD8+ T cells using CUT&RUN. CD8 T cells were sorted from the murine B16 melanoma tumor using PD1 and Tim3 expression to define four subsets: PD1lo, PD1mid, PD1hi, and PD1hiTim3+. Additional control samples include paired CD44+ cells from the tumor-draining lymph node of tumor bearing mice, and OT-I effector CD8 T cells isolated from Vaccinia-ova infection. We performed CUT&RUN for H3K4me3, H3K27me3, H3K27ac, and H3K9ac, as well as the transcription factors Tox and Batf.

2022-08-04 | GSE175437 | 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

Chimeric Antigen Receptors with a MyD88 and CD40 costimulatory endodomain endow T cells with superior antitumor activity

Project description:CAR T-cell therapy for solid tumors has shown limited efficacy in early phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains and we explored here if MyD88 and CD40 (MC) costimulatory endodomains in CARs improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T-cells and demonstrate that MC-CAR T-cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T-cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and are activated at base line. After stimulation, MC-CAR T-cells remain in a less differentiated state than CD28- and 41BB-CAR T-cells as judged by low levels of TBET and BLIMP1 expression, and lower cytolytic activity in comparison to CD28- and 41BB-CAR T-cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T-cell therapy approaches for solid tumors.

2020-09-18 | GSE158144 | GEO

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity III

Project description:Cytotoxic CD8+ T cells need to persist and function in diverse tumor microenvironments to exert their effects. Here, we developed Generalizable Matrix Decomposition Framework (GMDF), a matrix factorization algorithm that recovers both shared and tumor type-specific transcriptional programs from diverse data sets, and applied it to a scRNA-seq compendium of 38,852 CD8+ T cells from 141 patients spanning nine different human cancers. Our meta-single-cell analyses uncovered a pan-cancer T cell dysfunction program that was predictive of clinical responses to checkpoint blockade in melanoma and highlighted CXCR6 as a pan-cancer marker of chronically activated T cells. CXCR6 transcription was activated by AP-1 factors and repressed by TCF1. In mouse models, CXCR6 expression increased with tumor progression and upon checkpoint blockade. CXCR6 deletion in CD8+ T cells increased apoptosis of PD1+Tim3+ cells and compromised tumor growth control due to suppressed expression of survival factors and CD28 co-stimulation, revealing a role for CXCR6 in opposing PD1-mediated suppression of CD28 signaling. Our application of GMDF led us to discover a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity.

2024-07-02 | GSE234976 | GEO

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity II

2024-07-02 | GSE234975 | GEO

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity I

2024-07-02 | GSE234974 | GEO

Checkpoint blockade induced CD8+ T cell differentiation in responders in head and neck cancers

Project description:Background: Outcomes for locally advanced or recurrent/ metastatic head and neck squamous cell carcinomas (HNSCCs) remain unfavorable despite recent advances with immune checkpoint blockade (ICB). Preclinical studies using model antigens identified a critical role of CD8+TCF7+PD1+ T cells in anti-PD1 response. Studies on the heterogeneity and clonal dynamics of global tumor infiltrating T lymphocytes (TILs) in the HNSCC anti-PD1 and anti-CTLA4 response have not been explored. Results: In this study, we generated isogenic HNSCC anti-PD1 sensitive/resistant models that bore distinct cancer cell intrinsic transcriptomic programs. Tumor microenvironment characterization using mass cytometry and targeted depletion revealed the contribution of Tregs and M2-like macrophages in anti-PD1 resistance. Paired single-cell RNA and TCR sequencing on tumor infiltrating immune cells from ICB responsive and resistant HNSCC models identified a spectrum of CD8+ TIL subsets including TCF7+PD1- (naïve/memory-like), TCF7+PD1+ (progenitor exhausted), and TCF7-PD1+ (terminally exhausted). Mapping TCR shared fractions between these subsets identified that successful anti-PD1 or anti-CTLA4 therapy induced higher post-treatment T cell lineage transitions. A TIL differentiation gene signature was associated with better responses in multiple ICB clinical trials. Conclusions: Together, analyses integrating scRNAseq and TCRseq demonstrate distinct differentiation dynamics of CD8+ TILs in novel ICB responsive and resistant HNSCC models, highlighting critical aspects of CD8+ TIL differentiation in response to ICB.

2021-12-01 | GSE153383 | GEO

Cappuccio2006 - Cancer immunotherapy by interleukin-21

Project description:This model describes the effects of Il-21 on tumor eradication via natural killer cell-mediated and CD8+ T-cell-mediated lysis of tumor cells. The model demonstrates changes in growth dynamics in nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8+ T-cell balance on tumor immunogenicity.

2024-09-02 | BIOMD0000000761 | BioModels

NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment [CD4cre scRNA-seq]

Project description:Cytotoxic T cells (CTLs) play a crucial role in the elimination of cancer cells. However, within the intra-tumor microenvironment, these cells eventually undergo cell death or enter a state of dysfunction known as "exhaustion". T cell exhaustion not only impairs the efficacy of tumor immunity but also contributes to resistance against immune-checkpoint inhibitors. Our previous investigations have demonstrated that the NR4a family of nuclear receptors, induced by chronic TCR stimulation, plays a pivotal role in driving exhaustion. These receptors enhance the transcription of inhibitory molecules, such as PD1, while suppressing the expression of functional molecules, including cytokines. However, it remains unclear at which stage of T cell differentiation NR4a exerts its influence and whether the loss of NR4a can "rejuvenate" T cell fate. In the present study, we confirmed that simultaneous deletion of NR4a1 and NR4a2 in CD8+ T cells led to a less exhausted phenotype characterized by reduced expression of PD1, Tim3, and Tox, as well as increased oxidative phosphorylation (OXPHOS) and glycolysis activities, resulting in potent suppression of tumor growth. Interestingly, the transfer of activated NR4a1-/-NR4a2-/-CD8+ T cells into tumor-bearing mice gave rise to TCF1+ (Tcf7+) early memory T cells. Wild-type PD1+TIM3+CD8+ tumor-infiltrating lymphocytes (TILs) diminished in the secondary transfer to tumor-bearing mice, while NR4a-deficient CD8+ TILs expanded even during the secondary transfer, indicating a strong stemness of memory T cells due to NR4a loss. We discovered that NR4a directly repressed the expression of Tcf7 by binding to the enhancer region of the Tcf7 gene. Collectively, these findings indicate that inhibiting NR4a in tumors represents a potent strategy for immuno-oncotherapy by enhancing stemness and reducing exhaustion of memory T cells.

2024-02-02 | GSE247640 | GEO

NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment [scATAC-seq]

2024-02-02 | GSE242052 | GEO