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PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity

ABSTRACT: PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity

PROVIDER: PRJNA555118 | ENA |

REPOSITORIES: ENA

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PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity.

Project description:CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.

| S-EPMC6754306 | biostudies-literature

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

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

| PRJNA488638 | ENA

PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity

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

2019-07-17 | GSE134413 | 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

The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_ATACseq]

Project description:Immune checkpoint blockade is effective for some cancer patients, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets and in particular, the active site has been considered undruggable. Here, we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In murine cancer models resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes NK and CD8+ T cell function by enhancing JAK-STAT signaling and reducing T cell dysfunction. PTPN2/N1 inhibitors offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (NCT04777994). More broadly, our study shows that small molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics targeting this important class of enzymes.

2023-07-14 | GSE237376 | GEO

The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_RNAseq]

2023-07-14 | GSE237377 | GEO

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [SK_RNAseq]

Project description:AC484 is a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. In order to investigate the response of AC484 and IFNg treatment on wild type and PTPN2/N1 dual deletion B16F10 cells, these tumours were transcriptionally profiled.

2023-07-14 | GSE237371 | GEO

Exhausted-like CD8 resident memory T cells balance immunity and fibrotic sequelae

Project description:CD8 tissue-resident memory T cells (TRM) provide frontline immunity in mucosal tissues. The mechanisms regulating CD8 TRM maintenance, heterogeneity, protective and pathological functions are largely elusive. Here we identify an epitope-specific CD8 TRM population that is maintained by in situ MHC-I and B7 signaling following acute influenza infection. These TRM cells co-exhibit exhausted-like phenotypes and memory features, and provide heterologous immunity against secondary infection. PD-L1 blockade at the memory stage promotes exhausted-like TRM rejuvenation and secondary immunity at the cost of developing post-infection fibrotic sequelae. Increased numbers of CD8 TRM cells are observed in the lungs of pulmonary fibrosis patients compared to control patients. Thus, TRM exhaustion results from a tissue-specific cellular adaptation to balance fibrotic sequelae and secondary immunity.

2019-03-21 | GSE115786 | GEO

TIM-3 restrains anti-tumour immunity by regulating inflammasome activation.

Project description:TIM-3 restrains anti-tumour immunity by regulating inflammasome activation.

| PRJNA637635 | ENA