In:
PLOS ONE, Public Library of Science (PLoS), Vol. 15, No. 12 ( 2020-12-3), p. e0243145-
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 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0243145
DOI:
10.1371/journal.pone.0243145.g001
DOI:
10.1371/journal.pone.0243145.g002
DOI:
10.1371/journal.pone.0243145.g003
DOI:
10.1371/journal.pone.0243145.g004
DOI:
10.1371/journal.pone.0243145.g005
DOI:
10.1371/journal.pone.0243145.g006
DOI:
10.1371/journal.pone.0243145.g007
DOI:
10.1371/journal.pone.0243145.s001
DOI:
10.1371/journal.pone.0243145.s002
DOI:
10.1371/journal.pone.0243145.s003
DOI:
10.1371/journal.pone.0243145.s004
DOI:
10.1371/journal.pone.0243145.s005
DOI:
10.1371/journal.pone.0243145.s006
DOI:
10.1371/journal.pone.0243145.s007
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2267670-3
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