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

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

PROVIDER: PRJNA509668 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8313620.fastq.gz	Fastqsanger.gz
	SRR8313630.fastq.gz	Fastqsanger.gz
	SRR8313640.fastq.gz	Fastqsanger.gz
	SRR8313650.fastq.gz	Fastqsanger.gz
	SRR8313660.fastq.gz	Fastqsanger.gz

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

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

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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]

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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 transcription factors limit CAR-T cell function in solid tumors [RNA-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 | GSE123738 | GEO

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

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 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

The Second Generation of CAR-iMACs with Enhanced Polarization, CAR-mediated Efferocytosis and Superior Potency against Solid Tumors

Project description:Chimeric antigen receptor (CAR)-T cell therapies have shown great success in treating hematologic malignancies. Nonetheless, their therapeutic effect on solid tumors remains to be improved. Recently, macrophages have attracted great attention, given their ability to infiltrate solid tumors, phagocytize tumor cells as well as their immunomodulatory capacities. The first generation of CD3ζ-based CAR-macrophages demonstrated that the CAR could stimulate macrophage phagocytosis in a tumor antigen-dependent way. Here, we genetically engineered induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) with TLR4 intracellular TIR domain-containing CARs against EGFRvIII and GPC3, which yielded markedly enhanced antitumor effect in two different solid tumor models including glioblastoma, and hepatocellular carcinoma in which complete remission was achieved with CAR-iMACs alone or in combination with CD47 antibody. Moreover, the tandem CD3ζ-TIR-CAR, or the “second-generation” design of TIR-based dual signaling CAR, endowed iMACs with both target engulfment/efferocytosis capacity against antigen-expressing solid tumor cells, and potency of antigen-dependent M1 state polarization and M2 state resistance in an NF-κB dependent manner. We also illustrated a surprising mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we established the next generation CAR-iMACs equipped with orthogonal phagocytosis and polarization capacity for better antitumor functions in treating solid tumors.

2023-09-29 | GSE214140 | GEO

Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade

Project description:We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we developed clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduced tumor burden, prolonged survival, remodeled the TME, increased intratumoral T cell and natural killer (NK) cell infiltration, and induced epitope spreading. CAR-M therapy protected against antigen-negative relapse in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors resistant to anti-PD1(aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improved tumor growth control, survival, and remodeling of the TME. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to enhance response to aPD1 therapy for patients with non-responsive tumors.

2024-11-20 | GSE275417 | GEO

B7-H3-Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity Against Solid Tumors

Project description:Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen-presentation pathway, making them a potential “off-the-shelf” cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3-CAR-modified Vδ1T cells in treating solid tumors. Co-expression of interleukin-2 with the B7-H3-CAR led to durable anti-tumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells.Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors.

2024-08-22 | GSE275242 | GEO

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