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


ABSTRACT: 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)-? 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.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC7714195 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wang Yun Y   Zhang Kelvin K   Georgiev Peter P   Wells Steven S   Xu Haiyan H   Lacey Brian M BM   Xu Zangwei Z   Laskey Jason J   Mcleod Robbie R   Methot Joey L JL   Bittinger Mark M   Pasternak Alexander A   Ranganath Sheila S  

PloS one 20201203 12


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 intervent  ...[more]

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