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BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T-cell Stemness and Exhaustion

ABSTRACT: BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T-cell Stemness and Exhaustion

PROVIDER: PRJNA864848 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20738200_1.fastq.gz	Fastqsanger.gz
	SRR20738200_2.fastq.gz	Fastqsanger.gz
	SRR20738201_1.fastq.gz	Fastqsanger.gz
	SRR20738201_2.fastq.gz	Fastqsanger.gz
	SRR20738071_1.fastq.gz	Fastqsanger.gz

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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

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

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

| PRJNA864857 | ENA

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

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

| PRJNA864855 | ENA

BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion.

Project description:Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1, encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]-expressing CD8+ CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]-expressing CD8+ T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)-driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3+CD8+ and toward TCF1+CD8+ to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.

| S-EPMC10257143 | biostudies-literature

BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T-cell Stemness and Exhaustion

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

2022-08-04 | GSE210265 | GEO

BLIMP1 ChIPseq

Project description:BLIMP1 ChIPseq

| PRJEB1759 | ENA

Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

Project description:Abstract: Regulatory T cells (Tregs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Tregs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; a heterodimer of Ebi3 and IL12) are reciprocally expressed by Treg-subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. Treg-restricted deletion of either Il10/Ebi3 or dual deletion resulted in delayed tumor growth and significant reduction of transcriptomic exhaustion signature associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1). While the two cytokines share the BLIMP1 axis to drive multi-IR expression; they differentially impact effector vs. memory fate, highlighting their overlapping and non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated adaptive plasticity in inhibitory cytokine expression pattern by Tregs in TME for maximal immunosuppression. Data purpose: to understand the segregated cytokine expression pattern and the preferential generation of single cytokine positive Treg subpopulations, we performed single cell RNASeq (scRNAseq) contrasting Tregs isolated from naïve, unchallenged LNs or day 14 B16 tumor from Foxp3Cre-YFP WT mice

2019-04-02 | GSE126184 | GEO

BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells

Project description:To clarify the potential BLIMP1 downstream target regulating PD-L1 expression, we performed proteomics analysis using BLIMP1 Hep3B cells and control cells. Proteomics analysis revealed that SPI1 may serve as a pivotal transcriptional factor that enhances PD-L1 expression by acting as a downstream effector of BLIMP1.

2022-11-23 | PXD037621 | Pride

Gene expression profiles of mouse Blimp1 +/gfp and Blimp1 gfp/gfp regulatory T cells

Project description:Regulatory T (Treg) cells are required for peripheral tolerance. Recent evidence indicates that Treg cells can adopt specialized differentiation programs in the periphery that are controlled by transcription factors usually associated with T helper differentiation. We demonstrate that expression of the transcription factor Blimp1 defines a population of Treg cells that localize predominantly to mucosal sites and produces IL-10. Blimp1 is required for IL-10 production by these cells and for their tissue homeostasis. A list of differentially expressed genes were identified from this whole-genome expression profiling experiment. Mouse Blimp1 +/gfp and Blimp1 gfp/gfp regulatory T cells were analyzed. Three replicates each.

2011-02-09 | E-GEOD-27143 | biostudies-arrayexpress

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