2. Academic Validation
  3. VRK2 inhibition synergizes with PD-1 blockade to improve T cell responses

VRK2 inhibition synergizes with PD-1 blockade to improve T cell responses

  • Immunol Lett. 2021 May;233:42-47. doi: 10.1016/j.imlet.2021.03.007.
Michael Peled 1,  Anna S Tocheva 2,  Kieran Adam 3,  Adam Mor 4
Affiliations

Affiliations

  • 1 Institute of Pulmonary Medicine, Chaim Sheba Medical Center, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 2 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA.
  • 4 Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA; Division of Rheumatology, Columbia University Medical Center, New York, NY, 10032, USA. Electronic address: am5121@cumc.columbia.edu.
PMID: 33741379 DOI: 10.1016/j.imlet.2021.03.007
Abstract

Therapeutic programmed cell death protein 1 (PD-1) blockade enhances T cell mediated anti-tumor immunity but many patients do not respond and a significant proportion develops inflammatory toxicities. To develop better therapeutics and to understand the signaling pathways downstream of PD-1 we performed phosphoproteomic analysis of PD-1 and identified vaccinia related kinase 2 (VRK2) as a key mediator of PD-1 signaling. Using genetic and pharmacological approaches, we discovered that VRK2 is required for PD-1-induced phosphorylation of the protein p21 activated kinase 2 (PAK2), and for the inhibition of IL-2, IL-8, and IFN-γ secretion. Moving into in vivo syngeneic tumor models, pharmacologic inhibition of VRK2 in combination with PD-1 blockade enhanced tumor clearance through T cell activation. This study suggests that VRK2 is a unique therapeutic target and that combination of VRK2 inhibitors with PD-1 blockade may improve Cancer Immunotherapy.

Keywords

PD-1; T cell; TCR; VRK2.

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