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

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

PROVIDER: PRJNA647914 | ENA |

REPOSITORIES: ENA

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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

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 [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 [WGBS]

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

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FOXO1 is a master regulator of CAR T memory programming [RNA_Dual_OE-KO]

Project description:Poor CAR T persistence limits CAR T cell therapies for B cell malignancies and solid tumors1,2. The expression of memory-associated genes such as TCF7 (protein name TCF1) is linked to response and long-term persistence in patients3–7, thereby implicating memory programs in therapeutic efficacy. Here, we demonstrate that the pioneer transcription factor, FOXO1, is responsible for promoting memory programs and restraining exhaustion in human CAR T cells. Pharmacologic inhibition or gene editing of endogenous FOXO1 in human CAR T cells diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype, and impaired antitumor activity in vitro and in vivo. FOXO1 overexpression induced a gene expression program consistent with T cell memory and increased chromatin accessibility at FOXO1 binding motifs. FOXO1-overexpressing cells retained function, memory potential, and metabolic fitness during settings of chronic stimulation and exhibited enhanced persistence and antitumor activity in vivo. In contrast, TCF1 overexpression failed to enforce canonical memory programs or enhance CAR T cell potency. Importantly, endogenous FOXO1 activity correlated with CAR T and TIL responses in patients, underscoring its clinical relevance in cancer immunotherapy. Our results demonstrate that memory reprogramming through FOXO1 can enhance the persistence and potency of human CAR T cells and highlights the utility of pioneer factors, which bind condensed chromatin and induce local epigenetic remodeling, for optimizing therapeutic T cell states.

2024-02-29 | GSE255413 | GEO

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

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

| PRJNA648160 | ENA

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

FOXO1 is a master regulator of CAR T memory programming [RNA_Dual_OE-KO]

Project description:FOXO1 is a master regulator of CAR T memory programming [RNA_Dual_OE-KO]

| PRJNA1074824 | ENA

Effect of loss of Regnase-1 and Regnase-3 on the transcriptional profile in mouse Lin–Sca1+Kit+ (LSK) cells

Project description:Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that mRNA decay factors Regnase-1 (Zc3h12a) and Regnase-3 (Zc3h12c) are critical for induction of myeloid lineage priming, restricting lymphoid differentiation in HSPCs. Regnase-1- and Regnase-3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single cell-assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis revealed that Regnase-1 and Regnase-3 control the epigenetic landscape on myeloid-related gene loci in hematopoietic stem cells (HSCs) via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Regnase-1- and Regnase-3-mediated Nfkbiz mRNA degradation primed HSCs toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between post-transcriptional control and chromatin remodeling by the Regnase-1/Regnase-3-Nfkbiz axis governs lineage priming, instructing HSC lineage specification.

2024-02-09 | GSE228923 | GEO

Generation of clinical grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of B-cell malignancies

Project description:Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical grade tumor-redirected TSCM cells starting from naÃ¯ve precursors. CD8+CD62L+CD45RA+ naÃ¯ve T cells enriched by streptamer-based serial positive selection were activated by CD3/CD28 engagement in the presence of IL-7, IL-21 and the glycogen synthase-3Î² inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions allowed for the generation of CD19-CAR modified TSCM cells that were phenotypically, functionally and transcriptomically equivalent to their naturally occurring counterpart. Compared with T cell products currently under clinical investigation, CD19-CAR modified TSCM cells exhibit enhanced metabolic fitness, persistence and anti-tumor activity against systemic acute lymphoblastic leukemia xenografts. Based on these findings, we have initiated a phase 1 clinical study to evaluate the activity of CD19-CAR modified TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation. Three healthy human blood donors provided lymphocyte-enriched apheresis blood for this study after informed consent. From all samples, total RNA was isolated using an miRNeasy Mini Kit (Qiagen), processed by Ambionâ??s WT expression kit, fragmented and labeled with a WT Terminal Labeling Kit (Affymetrix), hybridized to WT Human Gene 1.0 ST arrays (Affymetrix) and stained on a Genechip Fluidics Station 450 (Affymetrix), all according to the respective manufacturer's instructions. Samples represent exon-level and gene-level analyses.

2016-06-29 | E-GEOD-68003 | biostudies-arrayexpress

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