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Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity

ABSTRACT: Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity

PROVIDER: PRJNA638673 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11991566.fastq.gz	Fastqsanger.gz
	SRR11991567.fastq.gz	Fastqsanger.gz
	SRR11991568.fastq.gz	Fastqsanger.gz
	SRR11991569.fastq.gz	Fastqsanger.gz
	SRR11991570.fastq.gz	Fastqsanger.gz

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Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [ATAC-Seq]

Project description:Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [ATAC-Seq]

| PRJNA638676 | ENA

Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [scRNA-Seq]

Project description:Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [scRNA-Seq]

| PRJNA638677 | ENA

Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [RNA-Seq]

Project description:Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [RNA-Seq]

| PRJNA638675 | ENA

Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [ATAC-Seq]

Project description:We report here that persistent activation of signal transducer and activator of transcription 5 (STAT5) in tumor-specific CD4+ T cells drives the development of polyfunctional T cells with superior antitumor activities. We showed that ectopic expression of a constitutively active form of murine STAT5A (CASTAT5) in tumor-specific CD4+ T cells established a distinct epigenetic and transcriptional landscape, endowing CD4+ T cells polyfunctionality, exhaustion-resistance and tumor-infiltrating capability. Single cell RNA sequencing analysis (scRNAseq) identified a subset of cells with the molecular signature indicative of their role as progenitor polyfunctional T cells. Importantly, T cells engineered to co-express CD19-targeting chimeric antigen receptors (CD19CAR) and CASTAT5 gave rise to polyfunctional CD4+ CAR T cells capable of providing optimal help to CD8+ T cells to achieve durable and curative outcomes in mice with advanced B-cell lymphoma. Evidence of CASTAT5 functional activities in primary human CD4+ T cells underscores its potential clinical relevance.

2020-10-22 | GSE152240 | GEO

Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [scRNA-Seq]

2020-10-22 | GSE152238 | GEO

Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity [RNA-Seq]

2020-10-22 | GSE152237 | GEO

Persistent STAT5 activation reprograms the epigenetic landscape in CD4<sup>+</sup> T cells to drive polyfunctionality and antitumor immunity.

Project description:The presence of polyfunctional CD4+ T cells is often associated with favorable antitumor immunity. We report here that persistent activation of signal transducer and activator of transcription 5 (STAT5) in tumor-specific CD4+ T cells drives the development of polyfunctional T cells. We showed that ectopic expression of a constitutively active form of murine STAT5A (CASTAT5) enabled tumor-specific CD4+ T cells to undergo robust expansion, infiltrate tumors vigorously, and elicit antitumor CD8+ T cell responses in a CD4+ T cell adoptive transfer model system. Integrated epigenomic and transcriptomic analysis revealed that CASTAT5 induced genome-wide chromatin remodeling in CD4+ T cells and established a distinct epigenetic and transcriptional landscape. Single-cell RNA sequencing analysis further identified a subset of CASTAT5-transduced CD4+ T cells with a molecular signature indicative of progenitor polyfunctional T cells. The therapeutic significance of CASTAT5 came from our finding that adoptive transfer of T cells engineered to coexpress CD19-targeting chimeric antigen receptor (CAR) and CASTAT5 gave rise to polyfunctional CD4+ CAR T cells in a mouse B cell lymphoma model. The optimal therapeutic outcome was obtained when both CD4+ and CD8+ CAR T cells were transduced with CASTAT5, indicating that CASTAT5 facilitates productive CD4 help to CD8+ T cells. Furthermore, we provide evidence that CASTAT5 is functional in primary human CD4+ T cells, underscoring its potential clinical relevance. Our results implicate STAT5 as a valid candidate for T cell engineering to generate polyfunctional, exhaustion-resistant, and tumor-tropic antitumor CD4+ T cells to potentiate adoptive T cell therapy for cancer.

| S-EPMC8265158 | biostudies-literature

Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity

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

2020-10-22 | GSE152242 | GEO

Activating Mutation in STAT5 Is Sufficient To Drive PTCL peripheral T-Cell Lymphoma (PTCL)

Project description:Recurrent gain-of-function mutations in the transcription factor STAT5 have been detected in PTCL, an aggressive, heterogeneous disease, for which currently no targeted therapy exists. Here we investigated whether constitutive activation of STAT5 suffices to drive PTCL and whether inhibition of the JAK/STAT pathway offers a novel therapeutic opportunity in this disease. We found pronounced STAT5 expression and activity in patients from different PTCL subsets. To mimic high STAT5 activity we expressed a hyperactive STAT5A variant (termed vcS5) in the hematopoietic lineage in transgenic mice. vcS5-transgenic animals developed a lethal PTCL-like disease with full penetrance, characterized by massive expansion of CD8+ T-cells and destructive organ-infiltration. Adoptive transfer of vcS5-expressing CD8+ T-cell rapidly induced the disease in immunocompetent recipient mice. Neoplastic vcS5-T-cells displayed cytokine-hypersensitivity and showed activated, memory CD8+ T-lymphocyte characteristics. Histo-pathological analysis as well as mRNA expression profiles of vcS5 mice was closely correlated with distinct human lymphoma subtypes, including PTCL. Treatment of murine and human PTCL cell lines with the clinical JAK inhibitor Ruxolitinib or a selective STAT5 SH2 domain inhibitor induced cell death. Thus, our results demonstrate that enhanced STAT5 signaling drives PTCL development and suggest inhibition of the JAK/STAT5 pathway as a valuable therapeutic option for patients suffering from these aggressive lymphomas.

2017-10-18 | GSE74176 | GEO

An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity

Project description:An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity

| PRJNA721231 | ENA