title: HPK1 as a novel target for cancer immunotherapy.
abstract: Identifying the appropriate drug targets for the development of a novel anti-tumor immunotherapy is one of the most risky steps in the drug development cycle. We have identified a hematopoietic cell-restricted serine/threonine kinase, hematopoietic progenitor kinase 1 (HPK1), as a possible target for therapeutic intervention. Targeted disruption of HPK1 alleles confers T cells with an elevated Th1 cytokine production in response to TCR engagement. HPK1                 (-/-) T cells proliferate more rapidly than the haplotype-matched wild-type counterpart and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1                 (-/-) T cells became resistant to lung tumor growth. Also, the loss of HPK1 from dendritic cells (DCs) endows them with superior antigen presentation ability, enabling HPK1                 (-/-) DCs to elicit a more potent anti-tumor immune response when used as cancer vaccine. It is probable that blocking the HPK1 kinase activity with a small molecule inhibitor may activate the superior anti-tumor activity of both cell types, resulting in a synergistic amplification of anti-tumor potential. Given that HPK1 is not expressed in any major organs, it is less likely that an inhibitor of HPK1 kinase activity would cause any serious side effects.
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Icahn 15-75B, New York, NY 10029, USA. sansana.sawasdikosol@mssm.edu
authors.forename: Sansana
authors.initials: S
authors.lastname: Sawasdikosol
authors.forename: Renyuan
authors.initials: R
authors.lastname: Zha
authors.forename: Boyu
authors.initials: B
authors.lastname: Yang
authors.forename: Steven
authors.initials: S
authors.lastname: Burakoff
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D009369:Neoplasms / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D015232:Dinoprostone