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NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [IN_VIVO_AW3]

ABSTRACT: NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [IN_VIVO_AW3]

PROVIDER: PRJNA854670 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19912836_1.fastq.gz	Fastqsanger.gz
	SRR19912836_2.fastq.gz	Fastqsanger.gz
	SRR19912837_1.fastq.gz	Fastqsanger.gz
	SRR19912837_2.fastq.gz	Fastqsanger.gz
	SRR19912838_1.fastq.gz	Fastqsanger.gz

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NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness

Project description:NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness

| PRJNA854666 | ENA

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [CULTURED_NCT07]

Project description:Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22 (IL-22), IL-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.

2022-07-03 | GSE207314 | GEO

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [IN_VIVO_AW3]

2022-07-03 | GSE207312 | GEO

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [CULTURED_NCT07]

Project description:NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [CULTURED_NCT07]

| PRJNA854669 | ENA

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness.

Project description: Not available

| S-EPMC9837446 | biostudies-literature

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-07-03 | GSE207315 | GEO

Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

Project description:Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

| PRJNA718568 | ENA

Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

Project description:One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine thatpotetiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I) that significantly promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex,as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigenprocessing activity of immunoproteasome, leading to enhanced major histocompatibility class I(MHC-I)-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation, empowers T-cell cytotoxicity, and thus elevates the tumorresponse to immunotherapy.

2021-03-31 | GSE171158 | GEO

NOTCH1 mediates a reciprocal switch between two distinct secretomes during senescence

Project description:Senescence, a persistent form of cell cycle arrest, is often associated with a diverse secretome, which provides complex downstream functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence (OIS) is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, whilst suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to ‘lateral induction of senescence’ through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. Because enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared to typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.

2016-08-03 | PXD004168 | Pride

Identification of ANXA1 as A Novel Upstream Negative Regulator of Notch1 Function in AML

Project description:Abnormal Notch1 expression has an important role in tumorigenesis. However, upstream control mechanisms for Notch1 are still insufficiently understood. Acute myeloid leukemia (AML) is one of the most common and lethal blood malignancies with limited possibilities for treatment. Thus, new therapeutic targets are urgently needed to improve current ineffective therapies. Herein, we found high Annexin A1 (ANXA1) expression was corelated with hyperproliferation of AML cells, and then we identified ANXA1 as a novel negative regulator of Notch1 function in AML. Mechanistically, ANXA1 directly bound to the intracellular domain of Notch1 (NICD) to target this tumor suppressor for degradation. Furthermore, NICD executed its tumor suppressive function through activation of the p15 promoter. Thus, ablation of the Notch1-p15-mediated tumor suppression by ANXA1 provided a novel mechanism of AML proliferation. In human AML patients, we discovered a mutual exclusive relation existed between ANXA1 and Notch1/p15, corroborating our mechanistic discovery. On the basis of these results, we reasonably speculate that targeting ANXA1 would provide an effective approach for treatment of AML. In support of this new therapeutic paradigm, we provided proof-of-concept data by antagonizing ANXA1 using NICD inhibitory peptides.

2024-10-03 | PXD056593 |

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