Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epigenetic profiles of chimeric antigen receptor T cells with knockout of PRDM1

ABSTRACT: Persistence of infused antitumor T cells is one of the essential factors for durable therapeutic response. T cells undergo genome-wide alterations in epigenetic architecture upon repeated antigen encounter, which is inevitably accompanied by progressive T cell differentiation and loss of longevity. In this study, we explored key epigenetic factors associated with terminal T cell differentiation using CRISPR/Cas9-mediated knockout of epigenetic genes in chimeric antigen receptor (CAR)-engineered human T cells and identified PRDM1 as one of the key epigenetic genes regulating T cell differentiation. We compared epigenetic profiles of control and PRDM1-knockout CAR-T cells by ATAC-sequencing analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173620 | GEO | 2022/05/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Gene expression profiles of chimeric antigen receptor T cells with knockout of epigenetic genes

Project description:Persistence of infused antitumor T cells is one of the essential factors for durable therapeutic response. T cells undergo genome-wide alterations in epigenetic architecture upon repeated antigen encounter, which is inevitably accompanied by progressive T cell differentiation and loss of longevity. In this study, we explored key epigenetic factors associated with terminal T cell differentiation using CRISPR/Cas9-mediated knockout of epigenetic genes in chimeric antigen receptor (CAR)-engineered human T cells and identified multiple key epigenetic genes. We analyzed gene expression profiles of CAR-T cells that were knocked out with the specific epigenetic genes by RNA-sequencing.

2022-05-17 | GSE173918 | GEO

Epigenetic profiles of chimeric antigen receptor T cells with knockout of PRDM1

Project description:Epigenetic profiles of chimeric antigen receptor T cells with knockout of PRDM1

| PRJNA726408 | ENA

Prdm1

Project description:Prdm1

| PRJNA300302 | ENA

BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T-cell Stemness and Exhaustion [RNA-Seq]

Project description:Chimeric antigen receptor (CAR) T-cells have not induced meaningful clinical responses in solid tumor indications. Loss of T-cell stemness, poor expansion capacity and exhaustion during prolonged tumor antigen exposure are major causes of CAR T-cell therapeutic resistance. scRNA-sequencing analysis of CAR T-cells from a first-in-human trial in metastatic prostate cancer identified two distinct and independently validated cell states associated with antitumor potency or lack of efficacy. Low levels of the PRDM1 gene encoding the BLIMP1 transcription factor defined highly potent TCF7+CD8+ CAR T-cells, while enrichment of TIM3+CD8+ T-cells with elevated PRDM1 expression predicted poor outcome. PRDM1 single knockout promoted TCF7-dependent CAR T-cell stemness and proliferation resulting in marginally enhanced leukemia control. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of NFAT-driven T-cell dysfunction characterized by compensatory upregulation of NR4A3 and multiple other genes encoding exhaustion-related transcription factors hampered effector function in solid tumors. PRDM1 and NR4A3 combined ablation skewed CAR T-cell phenotypes away from TIM3+CD8+ and toward TCF7+CD8+ to counter exhaustion of tumor-infiltrating CAR T-cells and improve in vivo antitumor responses, effects that were not achieved with BLIMP1 or NR4A3 single disruption alone. These data reveal a novel molecular targeting strategy to enrich stem-like CAR T-cells resistant to exhaustion and underscore dual inhibition of PRDM1/NR4A3 expression or activity as a promising approach to advance adoptive cell immuno-oncotherapy.

2022-08-04 | GSE210264 | GEO

BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T-cell Stemness and Exhaustion [ATAC-Seq]

2022-08-04 | GSE210262 | GEO

Gene expression profiles of chimeric cytokine receptor-engineered CAR-T cells

Project description:The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most of the cancer types , necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived IL-6 secretion. Thus, a novel approach to simultaneously enhance therapeutic efficacy and safety is warranted. In this study, we developed a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activate JAK-STAT pathway (G6/7R). CAR-T cells with G6/7R efficiently absorbed and degraded monocyte-derived IL-6 both in vitro and in vivo. The G6/7R-expressing CAR-T cells showed superior expansion and persistence in vivo, which resulted in durable antitumor response in multple tumor models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.

2024-03-24 | GSE216734 | GEO

Gene expression profiles of CAR-T cells engineered with chimeric cytokine receptors to induce JAK-STAT signaling

Project description:The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is insufficient in most cancers. However, enhancing the antitumor T cell response inevitably increases the risk of cytokine release syndrome associated with monocyte-derived IL-6 secretion. In this study, we developed a chimeric cytokine receptor consisting of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant (insertion of PPCL) (G6/7R). We also generated a modified receptor with the M452L mutation in the IL7R cytoplasmic domain (G6/7R-M452L). CAR-T cells with G6/7R or G6/7R-M452L efficiently absorbed monocyte-derived IL-6 and induced a superior therapeutic response compared to conventional CAR-T cells. Our strategy can be broadly applied to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.

2024-03-24 | GSE255145 | GEO

The transcriptional repressor Blimp1/Prdm1 regulates post-natal reprogramming of intestinal enterocytes

Project description:Expression profiling of Prdm1 mutant E18.5 small intestine was performed using Illumina whole genome V2 arrays. The hypothesis tested in the present study was that Blimp1 regulates the transcription of key genes involved in enterocyte differentiation and survival. Results identify substantial and premature activation of key components of the adult enterocyte biochemical signature. Villin-Cre and Prdm1BEH/+ animals were intercrossed to generate heterozygous Villin-Cre, Prdm1BEH males that were then mated with homozygous Prdm1 CA/CA females carrying the R26R allele to generate Prdm1+/+ (Prdm1CA/+) or Prdm1-/- (Villin-Cre, Prdm1CA/BEH) offspring. Total RNA obtained from 11 Prdm1+/+ and 10 Prdm1-/- E18.5 small intestine samples was hybridized to Illumina WG6_V2 beadchips.

2011-06-02 | E-GEOD-29658 | biostudies-arrayexpress

Comparative analysis of T cell receptor and chimeric antigen receptor signaling in primary CD8+ T cells

Project description:Chimeric antigen receptor-modified (CAR) T cell therapy targeting highly expressed lineage antigens is effective for B cell malignancies. Achieving durable efficacy for hematological malignancies and extending this therapeutic approach to solid tumors will require T cell recognition and elimination of tumor cells that may express lower levels of the CAR target antigen. Realizing this goal is challenging because current approaches to CAR design are largely empiric and detailed information on CAR signaling is only beginning to emerge. Synthetic CARs typically require hundreds of molecules on the target cell to initiate signaling, whereas natural T cell receptors (TCRs) can recognize less than ten peptide-MHC (pMHC) antigen complexes. We reasoned that in depth comparison of TCR and CAR stimulation-induced signaling events in primary T cells might guide rationale adaptations to CAR design that would improve antigen sensitivity. Bi-specific T cells possessing an endogenous TCR and exogenous CAR of defined specificity were formulated from healthy HLA-B8+ Epstein-Barr virus-seropositive donors. Bi-specific T cells were stimulated with magnetic microbeads coated with recombinant TCR or CAR antigen for 10, 45, or 90 minutes. Some bi-specific T cells were also left unstimulated and harvested at each timepoint to serve as controls. Altogether, 9 unique conditions were tested in an experiment and three independent experiments were performed.

2021-05-20 | PXD013734 | Pride

Expression analysis of chimeric antigen receptor-transduced T cells following antigenic stimulation

Project description:Adoptive transfer of anti-CD19 chimeric antigen receptor (CAR)-engineered T cells has shown impressive clinical responses in patients with refractory B-cell malignancies. However, therapeutic effects of CAR-T cells targeting other hematologic malignancies and solid tumors are not yet satisfactory. Although inefficient tumor trafficking and multiple immunosuppressive molecules impede CAR-T cell effector responses, signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals including T cell receptor (TCR) engagement (signal 1), costimulation (signal 2), and cytokine engagement (signal 3). CAR genes developed to date contain a CD3z domain and costimulatory domain(s), but not a domain to transmit signal 3. In this study, we have developed a novel CAR construct capable of inducing cytokine signaling in an antigen-dependent manner. The new generation CD19 CAR encodes a cytoplasmic domain of IL-2RB and STAT3-binding YXXQ motif together with CD3z and CD28 domains (28-IL2RB-z (YXXQ)). The 28-IL2RB-z (YXXQ) CAR-T cells showed antigen-dependent JAK-STAT, especially the STAT3-mediated pathway activation, which promoted their proliferation and prevented terminal differentiation. The 28-IL2RB-z (YXXQ) CAR-T cells demonstrated superior in vivo persistence and antileukemia effects compared with the currently used CARs in multiple tumor models.

2020-02-15 | GSE95037 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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