Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Timosaponin AIII enhances CAR-T cell potency and prevents relapse through impairing CAR-Tregs

ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy has become the standard treatment for refractory and relapsed (r/r) DLBCL in recent years. However, more than half of these patients develop primary or secondary resistance. Given that CAR Tregs are crucial in driving resistant and relapse to CAR-T therapy, but the strategies to overcome are limited. Here, we established a Treg functional high-throughput screening system and identified a natural product, currently in clinical trials, Timosaponin AIII (TAIII), impairs Treg function while activating T cell immune response during CAR-T therapy. Mechanistically, TAIII recruits and blocks the A2AR signaling in CAR-T cells as a novel allosteric inhibitor of A2AR, thereby eliminating CAR-Tregs by suppressing CREB-mediated FoxP3 transcription. Furthermore, TAIII suppresses tumor growth and improves the efficacy of PD-1 immunotherapy by reducing intratumoral Tregs in solid tumor models. Importantly, TAIII increases the Tcm percentage and enhances cytotoxic cytokine secretion of CAR-T cells post-infusion, improving their function. Combining or pretreating CAR-T cells with TAIII enhances their antitumor activity, thereby overcoming late relapses in lymphoma models. These results identify TAIII as a potent adjuvant for CAR-T cell function and manufacturing through eliminating CAR-Tregs proportion, thereby enabling CAR-T therapy to be applied with a broader perspective.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289388 | GEO | 2026/02/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Armoured CAR Tregs with PD1 promoter-driven IL-10 have enhanced suppressive function

Project description:The potency of regulatory T cell (Treg) therapy has been transformed through use of chimeric antigen receptors (CAR). However, to date, CAR Treg therapy has not achieved long-lasting tolerance in mouse models, suggesting that additional engineering is required to unlock the full potential of these cells. We previously found that human Tregs produce minimal amounts of IL-10 and have a limited capacity to control innate immunity in comparison to type I regulatory (Tr1) cells. Seeking to create “hybrid” CAR Tregs that were engineered with Tr1-like properties, we examined whether the PDCD1 locus could be exploited to endow Tregs with the ability to secrete high levels of IL-10 in a CAR-regulated manner.

2025-05-06 | GSE287328 | GEO

Mbd2 promotes Foxp3 demethylation and T-regulatory cell function

Project description:The proposed use of Foxp3+ T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmune diseases, or post-hemopoietic stem cell or organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3 expression. Conserved CpG dinucleotides in the Treg-specific demethylated region (TSDR) upstream of Foxp3 are demethylated only in stable, thymic-derived Foxp3+ Tregs. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to methylated sites, we tested whether targeting of Mbd2 might promote demethylation of Foxp3 and thereby promote Treg numbers or function. Surprisingly, while ChIP analysis showed Mbd2 binding to the Foxp3-associated TSDR site in Tregs, Mbd2 targeting by homologous recombination or siRNA decreased Treg numbers and impaired Treg suppressive function in vitro and in vivo. Moreover, we found complete TSDR demethylation in WT Tregs but >75% methylation in Mbd2-/- Tregs, whereas re-introduction of Mbd2 into Mbd2-null Tregs restored TSDR demethylation, Foxp3 gene expression and Treg suppressive function. Lastly, Mbd2-/- Tregs had markedly binding of the DNA demethylase enzyme, Tet2, in the TSDR region. These data show that Mbd2 has a key role in promoting TSDR demethylation, Foxp3 expression and Treg suppressive function. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of MBD2–/– mice, compared to wild type control (all Balb/c background).

2013-09-01 | E-GEOD-48653 | biostudies-arrayexpress

Tumor-site directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors. [human ATACseq]

Project description:The efficacy of Chimeric Antigen Receptor (CAR) T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment (TME) including adenosine, which suppresses CAR T cells through activation of the A2A receptor (A2AR). To overcome this, CAR T cells were engineered to express A1 receptor (A1R), a receptor that signals inversely to A2AR. Using murine and human CAR T cells, constitutive A1R overexpression was demonstrated to significantly enhance CAR T cell effector function albeit at the expense of CAR T cell persistence. Through a novel CRISPR/Cas9 “knock-in” approach we demonstrated that CAR T cells engineered to express A1R in a tumor-localized manner, led to enhanced anti-tumor efficacy dependent on the transcription factor IRF8 and was transcriptionally unique when compared to A2AR deletion. This data provides a novel approach for enhancing CAR T cell efficacy in solid tumors and provides proof of principle for site-directed expression of factors that promote effector T cell differentiation.

2025-03-16 | GSE284616 | GEO

Tumor-site directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors. [human RNAseq constitutive]

2025-03-16 | GSE284615 | GEO

Tumor-site directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors. [Human RNAseq inducible]

2025-03-16 | GSE284618 | GEO

Tumor-site directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors. [Mouse RNAseq constitutive]

2025-03-16 | GSE284614 | GEO

Tumor-site directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors. [CD8 inducible human RNAseq]

2025-03-16 | GSE284619 | GEO

Role of Adenosine 2A Receptors (A2AR) on regulatory T cells (Tregs)

Project description:The adenosine 2A receptor (A2AR) is expressed on regulatory T cells (Tregs), but the functional significance is currently unknown. We compared the gene expression between wild-type (WT) and A2AR knockout (KO) Tregs and between WT Tregs treated with vehicle or a selective A2AR agonist. FACS-sorted GFP positive Tregs from WT or A2AR KO FoxP3GFP mouse spleen and lymph nodes were incubated 18 hr with vehicle (DMSO), a separate set of WT Tregs were incubated with the selective A2AR agonist ATL1222 10 nM (Dogwood Pharmaceuticals, Inc.) for 18 hr prior to RNA isolation.

2012-05-31 | E-GEOD-34006 | biostudies-arrayexpress

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine. FACS purified Foxp3+ Tregs were stimulated in the presence of media or IL-27 to compare IL-27 induced gene profiles. Four samples (media stimulated or IL-27-stimulated) were collected from four independent experiments. Genes altered by IL-27 treatment were compared to those of media stimulated Tregs.

2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress

High affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells

Project description:Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T-cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28 activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3+ CAR Tregs uniquely acquiring CD40L surface expression and producing IFNγ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy.

2024-11-30 | GSE282623 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data