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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE154859 | GEO | 2021/07/08

REPOSITORIES: GEO

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

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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.

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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.

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

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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

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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.

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

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

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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.

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

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