| First Author | Wang Y | Year | 2020 |
| Journal | PLoS One | Volume | 15 |
| Issue | 12 | Pages | e0243145 |
| PubMed ID | 33270695 | Mgi Jnum | J:299209 |
| Mgi Id | MGI:6479538 | Doi | 10.1371/journal.pone.0243145 |
| Citation | Wang Y, et al. (2020) Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. PLoS One 15(12):e0243145 |
| abstractText | 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)-gamma 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. |
