Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

ABSTRACT: Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induces Tconv exhaustion, affects human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and transduced them with a non-TS CAR (CD19) or a TS-CAR (HA).

ORGANISM(S): Homo sapiens

PROVIDER: GSE209671 | GEO | 2022/07/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ATAC-seq profiling of human Tregs and conventional CD4+ cells that were transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induce Tconv exhaustion, affect human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and transduced them with a non-TS CAR (CD19) or a TS-CAR (HA).

2023-03-15 | GSE209835 | GEO

RNA-seq profiling of human Tregs and conventional CD4+ cells that were left untransduced or transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induce Tconv exhaustion, affect human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and either left them untransduced (UT) or transduced them with a non-TS CAR (CD19) or a TS-CAR (HA). After 12 days in culture, we isolated their RNA and did RNA sequencing.

2023-03-15 | GSE153384 | GEO

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

Project description:Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

| PRJNA862080 | ENA

Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [HiChIP]

Project description:Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.

2021-05-01 | GSE168881 | GEO

Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [ATAC-seq]

2021-05-01 | GSE168880 | GEO

Dasatinib enhances anti-tumor efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion

Project description:CD19-targeted Chimeric antigen receptor T cells (CART) cells have shown remarkable promise in various B cell malignancies. Sustained tonic signaling and antigen exposure drives CART cell differentiation and exhaustion, which limits the therapeutic potency and persistence of CART cells and is a major cause of CD19-expressing leukemia relapse after CD19-targeted CART cells treatment in ALL. Here, we systematically screened FDA approved tyrosine kinase inhibitors, and identified dasatinib as the best candidate to prevent or reverse both CD28/CART and 4-1BB/CART cells from differentiation and exhaustion during ex vivo expansion, which enhanced the therapeutic efficacy and in vivo persistence. Using RNA-seq, we identified the differentially expressed genes between dasatinib treated group and Nalm6 stimulated group, and found that memory-associated transcription factors TCF7 and naive/memory-associated cell surface marker CCR7 were upregulated, whereas exhaustion-related regulators (NR4A1, BATF3, ATF4 and FOS) and inhibitory receptors (PD1, LAG3) were down-regulated in dasatinib treated CAR T cells. Moreover, T cell activation associated signaling pathways (T cell receptor, Jak-STAT, MAPK and PI3K-Akt) which were upregulated in Nalm6 stimulated CART cells, showed fundamental downregulation in dasatinib treated CART cells. These findings imply that dasatinib played important roles in CART cell differentiation and exhaustion by inhibition of T cell activation pathways.

2021-06-03 | GSE151774 | GEO

Transient mTOR inhibition rescues 4-1BB-CAR-Tregs from tonic signal-induced dysfunction

Project description:Transient mTOR inhibition rescues 4-1BB-CAR-Tregs from tonic signal-induced dysfunction

| PRJNA761379 | ENA

High affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells

Project description:Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T-cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28 activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3+ CAR Tregs uniquely acquiring CD40L surface expression and producing IFNγ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy.

2024-11-30 | GSE282623 | GEO

Strong basal/tonic TCR signals are associated with chromatin accessibility changes in naive CD4+ T cells

Project description:Naïve T cells constantly experience TCR signals in response to self-peptides presented by MHC (pMHC) in vivo. The intensity of these basal or tonic TCR signals can be indirectly read out by expression of surrogate markers of tonic TCR signaling, including the Nur77-GFP transgene and Ly6c. The strength of tonic TCR signaling varies broadly across the naïve CD4+ T cell population and is correlated with functional heterogeneity.Cells that experience the most basal TCR signaling (Nur77-GFP hi, Ly6c lo) are hyporesponsive to peptide-MHC stimulation. Here we examine whether tonic TCR stimulation is associated with differences in chromatin accessibility.

2022-08-22 | GSE206072 | GEO

Strong basal/tonic TCR signals are associated with gene expression changes in naive CD4+ T cells

2022-08-22 | GSE206073 | GEO