2. Academic Validation
  3. SHP2 Targets ITK Downstream of PD-1 to Inhibit T Cell Function

SHP2 Targets ITK Downstream of PD-1 to Inhibit T Cell Function

  • Inflammation. 2021 Aug;44(4):1529-1539. doi: 10.1007/s10753-021-01437-8.
Marianne Strazza 1,  Kieran Adam 1,  Shalom Lerrer 1,  Johanna Straube 1,  Sabina Sandigursky 2,  Beatrix Ueberheide 3,  Adam Mor 4 5
Affiliations

Affiliations

  • 1 Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA.
  • 2 Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.
  • 3 Proteomics Laboratory, New York University School of Medicine, New York, NY, 10016, USA.
  • 4 Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA. am5121@cumc.columbia.edu.
  • 5 Division of Rheumatology, Columbia University Medical Center, New York, NY, 10032, USA. am5121@cumc.columbia.edu.
PMID: 33624224 DOI: 10.1007/s10753-021-01437-8
Abstract

PD-1 is a critical therapeutic target in Cancer Immunotherapy and Antibodies blocking PD-1 are approved for multiple types of malignancies. The Phosphatase SHP2 is the main effector mediating PD-1 downstream signaling and accordingly attempts have been made to target this Enzyme as an alternative approach to treat immunogenic tumors. Unfortunately, small molecule inhibitors of SHP2 do not work as expected, suggesting that the role of SHP2 in T cells is more complex than initially hypothesized. To better understand the perplexing role of SHP2 in T cells, we performed interactome mapping of SAP, an adapter protein that is associated with SHP2 downstream signaling. Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates Itk specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. This study suggests that Itk is a unique target in this pathway, and since Itk is a SHP2-dependent specific mediator of PD-1 signaling, the combination of Itk inhibitors with PD-1 blockade may improve upon PD-1 monotherapy in the treatment of Cancer.

Keywords

ITK; PD-1; SHP2; T cell receptor.

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