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CRISPR screening reveals targets to reprogram long-lived effector CD8+ T cells for cancer therapy [microarray]

ABSTRACT: CD8+ T cells can be reprogrammed for better persistence and robust effector function in TME. By performing an in vivo pooled CRISPR-Cas9 mutagenesis screening of metabolism-associated factors, we identify Regnase-1 as a major negative regulator of antitumor responses, whose deficiency results in drastically increased CD8+ T cell accumulation in tumors We used microarrays to compare the global transcription profiles of Regnase1-null, Ptpn2/Regnase1-null and Socs1/Regnase1-null tumor infiltrating CD8+ T cell populations

ORGANISM(S): Mus musculus

PROVIDER: GSE137016 | GEO | 2019/12/11

REPOSITORIES: GEO

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CRISPR screening reveals targets to reprogram long-lived effector CD8+ T cells for cancer therapy [scRNA-seq]

Project description:CD8+ T cells can be reprogrammed for better persistence and robust effector function in TME. By performing an in vivo pooled CRISPR-Cas9 mutagenesis screening of metabolism-associated factors, we identify Regnase-1 as a major negative regulator of antitumor responses, whose deficiency results in drastically increased CD8+ T cell accumulation in tumors

2019-12-11 | GSE137015 | GEO

CRISPR screening reveals targets to reprogram long-lived effector CD8+ T cells for cancer therapy [ATAC-seq]

2019-12-11 | GSE137014 | GEO

CRISPR screening reveals targets to reprogram long-lived effector CD8+ T cells for cancer therapy. [RNA-Seq]

2019-12-11 | GSE126071 | GEO

CRISPR screening reveals targets to reprogram long-lived effector CD8+ T cells for cancer therapy. [ATAC-Seq]

2019-12-11 | GSE126070 | GEO

Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs [ATAC-seq]

Project description:Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors and loss of PTPN2 promotes T cell expansion and CD4 and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Treg) plays a role in autoimmunity. Here we show that a reduction in Ptpn2 expression, comparable to that reported in human carriers of autoimmune-predisposing PTPN2 variants, unexpectedly enhances the severity of autoimmune arthritis through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, Ptpn2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORgt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17 associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in RORgt+ Treg and that loss of function of PTPN2 in Treg contributes to the association between PTPN2 and autoimmunity.

2019-03-18 | GSE123486 | GEO

Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs [RNA-seq]

2019-03-18 | GSE123484 | GEO

Haploinsufficiency in PTPN2 leads to early onset systemic autoimmunity from Evans syndrome to lupus

Project description:An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways downstream of several cytokine pathways. All identified mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro cytokine reporter and phosphatase assays, and by hyperproliferation of patients’ T cells stimulated with cytokines. Furthermore, patients exhibited high serum levels of various inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in various STAT factors. Flow cytometry analysis of patients’ blood cells revealed typical alterations associated with autoimmunity, such as an expansion of CD11c+ B cells and follicular helper T cells, and all patients presented with anti-platelet or other autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

2024-06-21 | GSE270302 | GEO

Ptpn2 regulates the generation of cytotoxic Tim-3+ CD8+ T cells and restrains anti-tumor immunity

Project description:Cellular and transcriptional experiments demonstrate that deletion of Ptpn2 enhances CD8+ T cell responses to chronic viral infection and cancer.

2019-07-17 | GSE119270 | GEO

Differential gene expression in WT mice and mice lacking PTPN2 in T cells

Project description:WT mice and mice lacking PTPN2 in T cells (PTPN2-CD4Cre mice) were treated with AOM/DSS to induce colorectal tumours. RNA was isolated from tumour and non-tumour tissues in the colon. Colon samples from water-treated WT and PTPN2-CD4Cre mice served as additional control. Total RNA was isolated and the samples sequenced for polyA enriched RNA.

2020-10-03 | E-MTAB-9629 | biostudies-arrayexpress

Impact of SOCS1 inactivation on Marilyn adoptive cell transfer in MB49 female C57BL/6 bearing mice

Project description:In vivo, the expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using an in vivo genome-wide CRISPR-Cas9 screen, we identified SOCS1 as a major non-redundant checkpoint imposing a brake on antigen experienced CD4+ T-cell proliferation upon antigen challenge. Although SOCS1 has been previously described as an inhibitor of CD8+ T-cell effector function, we highlight here that it is abrogating the CD4+ T-cell response. SOCS1 integrates several cytokines receptor signals to actively silence TCR-induced polycytokine signaling pathways, restraining CD4+ T cell proliferation and functions. Targeting SOCS1 in mouse and human CD4+ and CD8+ T cells improved the therapeutic efficacy of antitumor adoptive T-cell therapies, enhancing intra-tumor T cell accumulation, persistence and effector functions. SOCS1 deletion in CAR-T cells enhances CD4+ CAR T-cell proliferation/survival and polyfunctionality in vivo, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of re-stimulated CD4+ T cells, opening new possibilities to optimize adoptive T cell therapies.

2021-09-02 | GSE154791 | GEO

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