Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function.
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0243145 |
| _version_ | 1818360989145366528 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yun Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T21:09:33Z |
| format | Article |
| id | doaj.art-122f7b4dd63e4038920f174d5a32c1d4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T21:09:33Z |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-122f7b4dd63e4038920f174d5a32c1d42022-12-21T23:31:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-011512e024314510.1371/journal.pone.0243145Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function.Yun WangKelvin ZhangPeter GeorgievSteven WellsHaiyan XuBrian M LaceyZangwei XuJason LaskeyRobbie McleodJoey L MethotMark BittingerAlexander PasternakSheila RanganathHematopoietic 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.https://doi.org/10.1371/journal.pone.0243145 |
| spellingShingle | 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 Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. PLoS ONE |
| title | Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. |
| title_full | Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. |
| title_fullStr | Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. |
| title_full_unstemmed | Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. |
| title_short | Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. |
| title_sort | pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates t cell function |
| url | https://doi.org/10.1371/journal.pone.0243145 |
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