PLoS ONE (Jan 2020)

Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function.

  • Yun Wang,
  • Kelvin Zhang,
  • Peter Georgiev,
  • Steven Wells,
  • Haiyan Xu,
  • Brian M Lacey,
  • Zangwei Xu,
  • Jason Laskey,
  • Robbie Mcleod,
  • Joey L Methot,
  • Mark Bittinger,
  • Alexander Pasternak,
  • Sheila Ranganath

DOI
https://doi.org/10.1371/journal.pone.0243145
Journal volume & issue
Vol. 15, no. 12
p. e0243145

Abstract

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Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.