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 (+2 others)
2020 PLoS ONE  
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
more » ... acological 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.
doi:10.1371/journal.pone.0243145 pmid:33270695 fatcat:qnm5ytf4zrhnhngocnoe3aobde