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Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory [scRNA-Seq]

ABSTRACT: CAR T cells have been ineffective against solid tumors, where the hostile tumor microenvironment limits CAR T cell function and persistence. Here we have used CRISPR/Cas9 gene-editing, or a small molecule inhibitor to target protein tyrosine phosphatase N2 (PTPN2) in human CAR T cells specific for the Lewis Y (LeY) neo-antigen. Targeting PTPN2 increased CAR and cytokine signaling and enhanced the activation and cytotoxicity of anti-LeY CAR T cells. The deletion or the systemic inhibition of PTPN2 in human CAR T cells repressed the growth of human tumor xenografts or patient-derived xenografts in mice and prolonged survival. PTPN2 deletion or inhibition promoted the generation and intratumoral accumulation of stem cell memory CD8+ CAR T cells that are associated with persistent CAR T cell-mediated tumor repression and improved clinical outcomes in patients. These findings support the use of gene-editing or small molecule inhibitors for targeting PTPN2 in human CAR T cells to combat solid tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309443 | GEO | 2025/10/04

REPOSITORIES: GEO

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Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory [RNA-seq]

Project description:CAR T cells have been ineffective against solid tumors, where the hostile tumor microenvironment limits CAR T cell function and persistence. Here we have used CRISPR/Cas9 gene-editing, or a small molecule inhibitor to target protein tyrosine phosphatase N2 (PTPN2) in human CAR T cells specific for the Lewis Y (LeY) neo-antigen. Targeting PTPN2 increased CAR and cytokine signaling and enhanced the activation and cytotoxicity of anti-LeY CAR T cells. The deletion or the systemic inhibition of PTPN2 in human CAR T cells repressed the growth of human tumor xenografts or patient-derived xenografts in mice and prolonged survival. PTPN2 deletion or inhibition promoted the generation and intratumoral accumulation of stem cell memory CD8+ CAR T cells that are associated with persistent CAR T cell-mediated tumor repression and improved clinical outcomes in patients. These findings support the use of gene-editing or small molecule inhibitors for targeting PTPN2 in human CAR T cells to combat solid tumors.

2025-10-04 | GSE309442 | GEO

PTPN2 knockout vs WT

Project description:We generated pluripotent stem cells (Mel1 hESC containing a GFP reporter driven by the endogenous insulin promoter) with a functional knock out of PTPN2 by CRISPR/Cas9 genome editing. KO or WT control stem cells were differentiated into beta-like cells (sBC), sorted for GFP, and prepared for deep sequencing.

2022-11-30 | GSE211636 | 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

PTPN2 regulates metabolic flux to affect beta cell susceptibility to inflammatory stress

Project description:Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory environment, we generated a beta cell-specific deletion of Ptpn2 in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, streptozotocin (STZ) Ptpn2 βKO mice display marked increase in hyperglycemia and death due to exacerbated beta cell loss. Furthermore, cytokine treated Ptpn2 KO islets resulted in mitochondrial defects and reduced glucose-induced metabolic flux, suggesting beta cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to compromised metabolic fitness.

2023-12-01 | GSE215852 | 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

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

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 | GSE237377 | GEO

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

2023-07-14 | GSE237376 | GEO

Cytokine Stimulation of PTPN2-deleted cancer cells

Project description:PTPN2 was deleted from a selection of murine and human cancer cells using CRISPR/Cas9. The loss-of-function phenotype was assessed in vitro with cytokine stimulation or vehicle control.

2017-07-31 | GSE99299 | GEO

Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells

Project description:Poor tumor trafficking and the immunosuppressive tumor microenvironment (TME) limit chimeric antigen receptor (CAR) T cell efficacy in solid tumors, such as neuroblastoma. We previously optimized GPC2 CARs in human neuroblastoma xenografts leading to clinical translation, however, there have not been preclinical studies using immunocompetent models. Thus, here we generated murine GPC2 CAR T cells using the D3-GPC2-targeting single-chain variable fragment being utilized clinically (NCT05650749) and tested them in neuroblastoma syngeneic allografts. Immune profiling of GPC2 CAR T cell-treated tumors revealed significant reprogramming of the TME, most notably poor intra-tumor CAR T cell persistence being associated with increased recruitment of myeloid-derived suppressor cells (MDSCs), along with MDSC-recruiting CXCL1/2 chemokines. These tumor-infiltrating MDSCs directly inhibited GPC2 CAR T cell activation and proliferation ex vivo. To both capitalize on this chemokine gradient and mitigate MDSC-tumor trafficking, we engineered GPC2 CAR T cells to express the CXCL1/2 receptor, CXCR2. CXCR2-armored GPC2 CAR T cells migrated towards CXCL1/2 gradients, enhanced anti-neuroblastoma efficacy, and reduced the level of MDSCs in the TME. Together, these findings suggest CAR T cell studies in immunocompetent models are imperative to define mechanisms of solid tumor immune escape and rationally design armoring strategies that will lead to durable clinical efficacy.

2025-09-17 | GSE295013 | GEO

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