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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
SHP-1 phosphatase activity counteracts increased T cell receptor affinity
Michael Hebeisen1, Lukas Baitsch, Danilo Presotto
1Department of Oncology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland.
The Journal of Clinical Investigation
|February 9, 2013
Summary
High T cell receptor affinity boosts anti-tumor function, but too much impairs it. SHP-1 phosphatase inhibition enhances T cell responses, suggesting new immunotherapy strategies.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Therapy
Background:
- T cell receptor (TCR) affinity for peptide-MHC (pMHC) complexes is crucial for T cell function.
- Supraphysiological TCR-pMHC affinity paradoxically leads to diminished T cell activity.
Purpose of the Study:
- Investigate molecular mechanisms behind high-affinity T cell dysfunction.
- Identify targets for enhancing T cell-mediated anti-tumor immunity.
Main Methods:
- Engineered human CD8(+) T cells with varying TCR affinities for HLA-A2/NY-ESO-1.
- Assessed gene expression, signaling, receptor expression, and functional responses.
- Utilized programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade and SHP-1 inhibition (sodium stibogluconate).
Main Results:
- Supraphysiological TCR affinity impaired T cell gene expression, signaling, and co-stimulatory receptor levels.
- Programmed cell death-1 (PD-1) upregulation was highest at maximal TCR affinity.
- Src homology 2 domain-containing phosphatase 1 (SHP-1) upregulation increased with TCR affinity.
- SHP-1 inhibition broadly enhanced T cell function across affinities.
Conclusions:
- SHP-1 plays a global role in regulating CD8(+) T cell activation and responsiveness.
- Inhibiting protein tyrosine phosphatases like SHP-1 may enhance T cell-mediated immunity.
- Targeting SHP-1 offers a potential therapeutic strategy for cancer immunotherapy.
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