Open AccessPharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function
Author(s) -
Yun Wang,
Kelvin Zhang,
Peter Georgiev,
Steven B. Wells,
Haiyan Xu,
Brian M. Lacey,
Zangwei Xu,
Jason Laskey,
Robbie L. McLeod,
Joey L. Methot,
Mark Bittinger,
Alexander Pasternak,
Sheila Ranganath
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0243145
Subject(s) - microbiology and biotechnology , biology , cancer research , immune system , t cell , immunology
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 E 2 (PGE 2 ) 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.