The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity[PTPN2i-MS-scRNAseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE237375 | GEO | 2023/07/14
REPOSITORIES: GEO
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Project description:To assess TCR diversity in AC484-treated tumors we profiled the TCRβ chain repertoire from untreated, anti-PD-1-treated, or AC484-treated B16 tumours
2023-07-14 | GSE237374 | GEO
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.
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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.
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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.
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