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NR4a knock-down in HER2 CAR-T cells improves T cell longevity and promotes solid tumor eradication

ABSTRACT: NR4a knock-down in HER2 CAR-T cells improves T cell longevity and promotes solid tumor eradication

PROVIDER: PRJNA1008188 | ENA |

REPOSITORIES: ENA

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NR4a knock-down in HER2 CAR-T cells improves T cell longevity and promotes solid tumor eradication [RNA-Seq]

Project description:Chimeric antigen receptor (CAR)-T cell therapy targeting human CD19 have demonstrated clinical efficacy against B-cell malignancies. However, CAR-T cell therapy's efficacy against solid tumors is limited due to factors like low tumor-associated antigens, infiltration rate, and T cell exhaustion. We have shown that deleting NR4a genes in CAR-T cells prevents T cell exhaustion and improved their therapeutic effects on solid tumors in a mouse model. To further explore this for human, we deleted all three NR4a family factors in CAR-T cells that recognize Epidermal Growth Factor Receptor type 2 (HER2) using the CRISPR/Cas9 system. These modified CAR-T cells (NR4a-TKO CAR-T) exhibited resistance to exhaustion, increased tumor-killing activity, and higher efficacy in tumor regression and survival rate in a human lung carcinoma model in mice. The enhanced therapeutic effects were associated with increased cytokine expression, reduced exhaustion-related gene expression, and improved persistence within tumors. We propose that targeting NR4a could be a promising strategy for developing superior CAR-T cells against solid tumors.

2024-08-28 | GSE241456 | GEO

NR4a knock-down in HER2 CAR-T cells improves T cell longevity and promotes solid tumor eradication [RNA-Seq]

Project description:NR4a knock-down in HER2 CAR-T cells improves T cell longevity and promotes solid tumor eradication [RNA-Seq]

| PRJNA1008189 | ENA

NR4a knock-down in HER2 CAR-T cells improves T cell longevity and promotes solid tumor eradication

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-08-30 | GSE241458 | GEO

Gene expression profiles of wild type and Nr4a-triple knockout (Nr4a-TKO) Tnaive and iTreg 3 h

Project description:In this study, we investigated the roles of Nr4a family transcription factors in Th and Treg cell differentiation from Tnaive cells. Nr4a factors were found to promote Treg cell differentiation and repress Th1 and Th2 differentiation. During Treg cell differentiation, all Nr4a factors are transiently induced in Tnaive cells immediately after TCR stimulation, whereby they mediate epigenetic changes directly or by cooperating with other transcription factors. To reveal Nr4a factors' mediated transcrptional events, we analyzed gene expression of wild type and Nr4a-tripple knockout (Nr4a-TKO) Tnaive and iTreg cells by microarray analysis.

2020-07-08 | GSE153926 | GEO

Gene expression profiles of wild type, Nr4a-triple knockout (Nr4a-TKO), and Foxp3-KO iTreg 24 h

Project description:In this study, we investigated the roles of Nr4a family transcription factors in Th and Treg cell differentiation from Tnaive cells. Nr4a factors were found to promote Treg cell differentiation and repress Th1 and Th2 differentiation. During Treg cell differentiation, all Nr4a factors are transiently induced in Tnaive cells immediately after TCR stimulation, whereby they mediate epigenetic changes directly or by cooperating with other transcription factors. To reveal Nr4a factors' mediated transcrptional events, we analyzed gene expression of wild type and Nr4a1,a2,a3-tripple knockout (Nr4a-TKO) iTreg cells by microarray analysis.

2020-07-08 | GSE153927 | GEO

Comparison of mRNA expression pattern between wild-type regulatory T (Treg) cells and Nr4a-deficient Treg cells

Project description:Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system physiology and pathophysiology. Treg cells are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. However, the molecular mechanisms that establish and/or maintain such gene regulation in Treg cells remain largely unknown. We recently reported that Nr4a family nuclear orphan receptors are essential for the development of Treg cells. The fact that Treg cells maintain high levels of expression of all Nr4a family components suggests that they may also play critical roles beyond Treg cell development. Thus, we compared mRNA expression pattern between wild-type Treg cells and Nr4a-deficietn Treg cells. As a result, we found that expression of 'Treg-signature genes' were globally down regulated in Nr4a-deficient Treg cells. mRNA from wild-type and Nr4a-deficient Treg cells were analyzed.

2015-06-27 | E-GEOD-70306 | biostudies-arrayexpress

Involvement of Nr4a in a Treg-specific transcriptional program and suppression ofM-cM-^@M-^@Th2/Tfh response

Project description:Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system physiology and pathophysiology. Treg cells are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. However, the molecular mechanisms that establish and/or maintain such gene regulation in Treg cells remain largely unknown. We recently reported that Nr4a family nuclear orphan receptors are essential for the development of Treg cells. The fact that Treg cells maintain high levels of expression of all Nr4a family components suggests that they may also play critical roles beyond Treg cell development. Here, we show that Nr4a factors are essential for maintaining Treg-specific gene expression programs, mediating two defined characteristics of Treg cells: lineage stability and suppressive activity. A compound knockout mouse strain in which all Nr4a genes were specifically deleted in Treg cells developed systemic immunopathology with accelerated Th2/Tfh/IgE reactions. Treg cells in these mice showed global reduction of 'Treg signature' gene expression, including Foxp3, Il2ra and Ikzf4. These findings demonstrate that Nr4a controls a genetic program indispensable for Treg cell maintenance and function. mRNA from wild-type and Nr4a-deficient Treg cells were analyzed.

2013-12-23 | E-GEOD-53574 | biostudies-arrayexpress

Genome wide mapping of NR4A binding reveals cooperativity with ETS factors to promote epigenetic activation of distal enhancers in acute myeloid leukemia cells [array]

Project description:NR4As are critical tumor suppressors of acute myeloid leukemia (AML) whose expression is broadly silenced in leukemia initiating cell enriched populations from human patients relative to normal hematopoietic stem/progenitor cells. Rescued NR4A expression in human AML cells inhibits proliferation and reprograms AML gene signatures via transcriptional mechanisms that remain to be elucidated. By intersecting an acutely regulated, NR4A1 dependent transcriptional profile with genome wide NR4A binding distribution, we now identify an NR4A targetome of 685 genes that are directly regulated by NR4A1. We show that NR4As regulate gene transcription primarily through interaction with distal enhancers that are co-enriched for both NR4A1 and ETS transcription factor motifs. Using a subset of NR4A activated genes, we demonstrate that the ETS factors ERG and FLI-1 are required for activation of NR4A bound enhancers and NR4A target gene induction. NR4A1 dependent recruitment of ERG and FLI-1 promotes binding of p300 histone acetyl transferase to activate NR4A bound enhancers. These findings disclose novel epigenetic mechanisms by which NR4As and ETS factors cooperate to drive NR4A dependent gene transcription in human AML cells. Transcriptome analysis in triplicate 6hr after exogenous NR4A1 expression compared to GFP transfection control.

2016-03-22 | E-GEOD-79490 | biostudies-arrayexpress

Genome wide mapping of NR4A binding reveals cooperativity with ETS factors to promote epigenetic activation of distal enhancers in acute myeloid leukemia cells [ChIP-Seq]

2016-03-22 | E-GEOD-79491 | biostudies-arrayexpress

Nr4a transcription factors limit CAR-T cell function in solid tumors

Project description:Nr4a transcription factors limit CAR-T cell function in solid tumors

| PRJNA509664 | ENA