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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226522 | GEO | 2023/03/15

REPOSITORIES: GEO

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

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

| PRJNA940474 | ENA

The RNA-binding proteins Roquin-1 and Regnase-1 interact and cooperate to prevent autoimmunity

Project description:This study aimed to analyze the transcriptomic changes occuring after knockout of alleles encoding for the RNA-binding proteins Roquin-1 and Roquin-2 (DKO), Regnase-1 (KO) or a combination of all three (TKO) in Th1 cells without or after restimulation with anti-CD3/28 antibodies. Data analysis revealed that in unstimulated as well as restimulated T cells of all three knockout genotypes a number of genes is differentially expressed compared to WT cells, with the strongest deregulation seen in TKO cells. A comparison of gene expression changes of all three genotypes indicated that cooperativity of Roquin and Regnase-1 is the prevalent mode of target regulation.

2020-06-23 | GSE152961 | GEO

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

Project description:A fundamental limitation of T cell therapies in solid tumors is loss of inflammatory effector functions, such as cytokine production and proliferation. Here, we target a regulatory axis of T cell inflammatory responses, Regnase-1 and Roquin-1, to enhance antitumor responses in human T cells engineered with two clinical-stage immune receptors. Building on previous observations of Regnase-1 or Roquin-1 knockout in murine T cells or in human T cells for hematological malignancy models, we found that knockout of either Regnase-1 or Roquin-1 alone enhances antitumor function in solid tumor models, but that knockout of both Regnase-1 and Roquin-1 increases function further than knockout of either regulator alone. Double knockout of Regnase-1 and Roquin-1 increased resting T cell inflammatory activity and led to at least an order of magnitude greater T cell expansion and accumulation in xenograft mouse models, increased cytokine activity, and persistence. However double knockout of Regnase-1 and Roguin-1 also led to a lymphoproliferative syndrome and toxicity in some mice. These results suggest that regulators of immune inflammatory functions may be interesting targets to modulate to improve antitumor responses.

| S-EPMC10041166 | 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 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

Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses.

Project description:Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies.

| S-EPMC8996344 | biostudies-literature

Analysis of Roquin targetome during HCMV infection

Project description:To investigate how Roquin regulates cellular transcripts during Human cytomegalovirus (HCMV) infection, we examined the levels of cellular transcripts in cells treated control or Roquin-targeting siRNA during HCMV replication. Also, we performed Roquin crosslinking and immunoprecipitation followed by high-throughput sequencing (Roquin CLIP-seq) in HCMV-infected cells to identify which transcripts are directly bound by Roquin.

2019-08-15 | GSE132081 | GEO

The RNA-binding proteins Roquin-1 and Regnase-1 interact and cooperate to prevent autoimmunity

Project description:The RNA-binding proteins Roquin-1 and Regnase-1 interact and cooperate to prevent autoimmunity

| PRJNA641085 | ENA

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

2021-07-21 | GSE171442 | 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

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