Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions

ABSTRACT: Differential gene expression profiling of CD19CAR-T cell incorporated B-cell costimulatory signaling domain

PROVIDER: PRJEB57053 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	ERR10447814_1.fastq.gz	Fastqsanger.gz
	ERR10447814_2.fastq.gz	Fastqsanger.gz
	ERR10447815_1.fastq.gz	Fastqsanger.gz
	ERR10447815_2.fastq.gz	Fastqsanger.gz
	ERR10447816_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 18

Similar Datasets

Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions.

Project description:CD19 chimeric antigen receptor (CAR) T-cells have demonstrated remarkable outcomes in B-cell malignancies. Recently, the novel CD19CAR-T cells incorporated with B-cell costimulatory molecules of CD79A/CD40 demonstrated superior antitumor activity in the B-cell lymphoma model compared with CD28 or 4-1BB. Here, we investigated the intrinsic transcriptional gene underlying the functional advantage of CD19.79A.40z CAR-T cells following CD19 antigen exposure using transcriptome analysis compared to CD28 or 4-1BB. Notably, CD19.79A.40z CAR-T cells up-regulated genes involved in T-cell activation, T-cell proliferation, and NF-κB signaling, whereas down-regulated genes associated with T-cell exhaustion and apoptosis. Interestingly, CD19.79A.40z CAR- and CD19.BBz CAR-T cells were enriched in almost similar pathways. Furthermore, gene set enrichment analysis demonstrated the enrichment of genes, which were previously identified to correlate with T-cell proliferation, interferon signaling pathway, and naïve and memory T-cell signatures, and down-regulated T-cell exhaustion genes in CD79A/CD40, compared with the T-cell costimulatory domain. The CD19.79A.40z CAR-T cells also up-regulated genes related to glycolysis and fatty acid metabolism, which are necessary to drive T-cell proliferation and differentiation compared with conventional CD19CAR-T cells. Our study provides a comprehensive insight into the understanding of gene signatures that potentiates the superior antitumor functions by CD19CAR-T cells incorporated with the CD79A/CD40 costimulatory domain.

| S-EPMC9729744 | biostudies-literature

A Phase 1/2 Trial of TC-510 In Patients With Advanced Mesothelin-Expressing Cancer

Project description:TC-510 is a novel cell therapy that consists of autologous genetically engineered T cells expressing two synthetic constructs: first, a single-domain antibody that recognizes human Mesothelin, fused to the CD3-epsilon subunit which, upon expression, is incorporated into the endogenous T cell receptor (TCR) complex and second, a PD-1:CD28 switch receptor, which is expressed on the surface of the T cell, independently from the TCR. The PD-1:CD28 switch receptor comprises the PD-1 extracellular domain fused to the CD28 intracellular domain via a transmembrane domain. Thus, the switch is designed to produce a costimulatory signal upon engagement with PD-L1 on cancer cells.

| 2740481 | ecrin-mdr-crc

Gene expression in self-activating CAR-T cells with CD28 or 4-1BB costimulatory domain and G4S or Whilow218 linker.

Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. Changes in the gene expression by substituting (G4S)4 linker in scFv portion to Whitlow 218 linker was investigated.

2024-09-16 | GSE276932 | GEO

Gene expression in self-activating- and non-self-activationg CAR-T cells with CD28 or 4-1BB costimulatory domain.

Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. To elucidate molecules responsible for self-activation-induced exhaustion, we performed RNA-seq analysis of SKM-CAR-T cells with CD28 or 4-1BB and CD19-CAR-T cells with CD28 or 4-1BB.

2022-08-19 | GSE211352 | GEO

Gene expression in self-activating CAR-T cells with CD28 or 4-1BB costimulatory domains.

Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. Changes in the gene expression by substituting CD28 co-stimulatory domain to 4-1BB co-stimulatory domain was investigated.

2023-05-28 | GSE231443 | GEO

Chimeric Antigen Receptors with a MyD88 and CD40 costimulatory endodomain endow T cells with superior antitumor activity

Project description:CAR T-cell therapy for solid tumors has shown limited efficacy in early phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains and we explored here if MyD88 and CD40 (MC) costimulatory endodomains in CARs improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T-cells and demonstrate that MC-CAR T-cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T-cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and are activated at base line. After stimulation, MC-CAR T-cells remain in a less differentiated state than CD28- and 41BB-CAR T-cells as judged by low levels of TBET and BLIMP1 expression, and lower cytolytic activity in comparison to CD28- and 41BB-CAR T-cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T-cell therapy approaches for solid tumors.

2020-09-18 | GSE158144 | GEO

Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction

Project description:Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction

| PRJNA963196 | ENA

Optimal pairing of binder and costimulatory domains improves dual CAR T cell efficacy

Project description:We explore whether introducing two chimeric antigen receptor (CAR) molecules with distinct signaling motifs into a single T cell improves CAR T cell (CART) efficacy against leukemia and lymphoma. RNA expression profiling demonstrated that T cells co-expressing two CARs that recognize the same target in which one CAR was linked to CD28 costimulation and the other was linked to 4-1BB costimulation augmented canonical NF-κB, non-canonical NF-κB, and Th17 differentiation pathways equivalently upon target engagement. Interestingly, multitargeted CARTs transcriptional profile favored the costimulatory domain linked to the binder of the more robustly expressed CD19 rather than one linked to the binder of the less expressed CD22 upon tumor engagement. In vivo and T cell exhaustion assays found that multitargeted T cells with distinct signaling domains led to greater durable control of B-ALL than single targeted Dual CAR T cells with T cells co-expressing CD19.BBζ and CD22.28ζ being the most potent. Together, this data indicates that optimal pairing of CAR binder domain with signaling cassette bolsters anti-tumor efficacy by improving both T cell durability and effector function.

2025-08-13 | GSE296016 | GEO

CD40/CD154 blockade inhibits dendritic cell expression of inflammatory cytokines but not costimulatory molecules.

Project description:Blockade of the CD40/CD154 pathway remains one of the most effective means of promoting graft survival following transplantation. However, the effects of CD40/CD154 antagonism on dendritic cell (DC) phenotype and functionality following transplantation remain incompletely understood. To dissect the effects of CD154/CD40 blockade on DC activation in vivo, we generated hematopoietic chimeras in mice that expressed a surrogate minor Ag (OVA). Adoptive transfer of OVA-specific CD4(+) and CD8(+) T cells led to chimerism rejection, which was inhibited by treatment with CD154 blockade. Surprisingly, CD154 antagonism did not alter the expression of MHC and costimulatory molecules on CD11c(+) DCs compared with untreated controls. However, DCs isolated from anti-CD154-treated animals exhibited a significant reduction in inflammatory cytokine secretion. Combined blockade of inflammatory cytokines IL-6 and IL-12p40 attenuated the expansion of Ag-specific CD4(+) and CD8(+) T cells and transiently inhibited the rejection of OVA-expressing cells. These results suggest that a major effect of CD154 antagonism in vivo is an impairment in the provision of signal three during donor-reactive T cell programming, as opposed to an impact on the provision of signal two. We conclude that therapies designed to target inflammatory cytokines during donor-reactive T cell activation may be beneficial in attenuating these responses and prolonging graft survival.

| S-EPMC3478479 | biostudies-literature

Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [RNA-seq]

Project description:Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [RNA-seq]

| PRJNA963195 | ENA