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Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL [WGBS]

ABSTRACT: Defciency of Regnase-1 enhances CAR-T cell persistence and anti-tumor ability

ORGANISM(S): Mus musculus

PROVIDER: GSE171442 | GEO | 2021/07/21

REPOSITORIES: GEO

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Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL [Microarray Expression]

Project description:transcriptional profiling was performed on WT and KO CAR T cells isolated 7 days after co-transfer into mice with or without tumors. Regnase-1 KO CAR T cells undergoing a tumor-dependent shift from an effector to memory-like phenotype

2021-07-08 | GSE154859 | GEO

Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL.

Project description:Chimeric antigen receptor (CAR)-T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR-T-cell expansion and memory-like cell formation. This leads to improved CAR-T-mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1-deficient CAR-T cells into TCF-1+ precursor exhausted T cells (TPEX) characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 messenger RNA (mRNA); its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR-T-cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1- CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR-T-cell population. Our findings demonstrate the pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR-T-cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR-T-cell longevity and potency that may be manipulated for improved therapeutic efficacy.

| S-EPMC8288655 | biostudies-literature

Improved persistence and expanded TPEX formation in Regnase-1 KO CAR T cells is TCF-1-dependent

Project description:transcriptional profiling was performed on Regnase-1 KO CAR and Regnase-1 TCF-1 DKO CAR T cells isolated 7days after co-transfer into tumor bearing mice. TCF-1 deficiency in Regnase-1 KO CAR T cells led to reduced long-term persistence and memory-like phenotype.

2021-04-07 | GSE155020 | GEO

Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL [WGBS]

Project description:Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL [WGBS]

| PRJNA719647 | ENA

Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL

Project description:Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL

| PRJNA648158 | ENA

Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL

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

2021-04-07 | GSE155021 | GEO

Regnase-1 KO CAR T cell reprogramed to memory-like cells

Project description:transcriptional profiling was performed on WT and KO CAR T cells isolated 21 days after co-transfer into tumor bearing mice. Regnase-1 KO CAR T cell reprogramed to memory-like cells long-term after tumor priming in vivo compared to WT CAR T cells

2021-07-08 | GSE154942 | GEO

Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL [Microarray Expression]

Project description:Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL [Microarray Expression]

| PRJNA647751 | ENA

Zheng W, Wei J, Zebley CC, et al. Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. 2021;138(2):122-135.

Project description: Not available

| S-EPMC8952182 | biostudies-literature

Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells

Project description:To investigate the effect of Regnase-1 and/or Roquin-1 disruption in engineered primary human T cells, we produced CAR-T cells and TCR-T cells with single genetic disruption of Regnase-1, Roquin-1, or dual disruption of Regnase-1 and Roquin-1. We then performed differential gene expression analysis using data obtained from bulk RNA-seq of 3 different biological donors at baseline.

2023-03-15 | GSE226522 | GEO

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