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Nr4a transcription factors limit CAR-T cell function in solid tumors [RNA-Seq]

ABSTRACT: Chromatin accessibility with ATAC-seq and gene expression with RNA-seq for CD8 T cells expressing chimeric antigen receptors in solid tumors or after in vitro culture.

ORGANISM(S): Mus musculus

PROVIDER: GSE123738 | GEO | 2019/02/13

REPOSITORIES: GEO

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Nr4a transcription factors limit CAR-T cell function in solid tumors [ATAC-Seq]

Project description:Chromatin accessibility with ATAC-seq and gene expression with RNA-seq for CD8 T cells expressing chimeric antigen receptors in solid tumors or after in vitro culture.

2019-02-13 | GSE123629 | GEO

Nr4a transcription factors limit CAR-T cell function in solid tumors [ATAC-Seq]

Project description:Nr4a transcription factors limit CAR-T cell function in solid tumors [ATAC-Seq]

| PRJNA509426 | ENA

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

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

2019-02-13 | GSE123739 | GEO

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

NR4A transcription factors limit CAR T cell function in solid tumours.

Project description:T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies1,2. CAR T cells have been less effective against solid tumours3-5, in part because they enter a hyporesponsive ('exhausted' or 'dysfunctional') state6-9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19+ tumour-bearing mice. CD8+CAR+ tumour-infiltrating lymphocytes and CD8+ endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)10-12. CD8+ T cells from humans with cancer or chronic viral infections13-15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8+ effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.

| S-EPMC6546093 | biostudies-literature

Nr4a transcription factors limit CAR-T cell function in solid tumors [RNA-Seq]

Project description:Nr4a transcription factors limit CAR-T cell function in solid tumors [RNA-Seq]

| PRJNA509668 | ENA

Sensitive CAR T cells redefine targetable CD70 expression in solid tumors [Multiomics]

Project description:Overcoming tumor antigen heterogeneity in solid tumors is a major challenge for cancer immunotherapies including chimeric antigen receptor (CAR) T cells. Unlike CD19 for B-cell malignancies, no target with pan-cellular expression in solid tumors and absence in normal vital cells has been identified. CD70 is a potential candidate, confined to immune cell subsets and aberrantly expressed in many solid tumors, albeit heterogeneously. We find that CD70 expression in heterogeneous tumors is not binary but ranges from high to very low, appearing negative. We show that CD70-heterogeneous tumors are efficiently eliminated by highly sensitive CD70 receptors where prototypic CAR T cells fail. We further identify an epigenetic signature that predicts targetable expression. These findings provide a potential strategy to treat a broad range of solid tumors.

2026-02-26 | GSE306275 | GEO

Sensitive CAR T cells redefine targetable CD70 expression in solid tumors [ATAC-seq]

Project description:CD70 expression in solid tumors is heterogeneous. We demonstrate that cells appearing CD70-negative retain ultra-low levels of CD70 expression. These cells that appear negative by conventional detection methods. Bulk ATAC-seq analysis of FACS-sorted CD70⁻ and CD70⁺ tumor populations revealed differential chromatin accessibility, indicating epigenetic regulation of CD70 expression in both ccRCC and HGSOC models.

2026-02-26 | GSE311096 | GEO

Sensitive CAR T cells redefine targetable CD70 expression in solid tumors [CITE-seq]

2026-02-26 | GSE306608 | GEO

OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumors

Project description:Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumors but remain limited by poor tumor infiltration, persistence, and resistance within the tumor microenvironment (TME). To identify gain-of-function (GOF) targets that enhance CAR-NK efficacy, we performed an unbiased in vivo Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) activation (CRISPRa) screen, followed by a barcoded targeted in vivo open reading frame (ORF) screen in primary human CAR-NK cells. We identified, and robustly validated OR7A10, a G protein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NKs with OR7A10 cDNA, a CRISPR-independent method with simple manufacturing strategy, enhanced proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness, and TME resistance, while reducing exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors. OR7A10-GOF CAR-NKs displayed robust in vivo efficacy across multiple solid tumor models, achieving a 100% complete response in an orthotopic breast cancer model with long term tumor control and survival benefit. These findings establish OR7A10-engineered CAR-NKs as a highly potent and scalable off-the-shelf therapeutic for solid tumors.

2025-12-17 | GSE310267 | GEO

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