HPK1 as a novel target for cancer immunotherapy

The Structure of HPK1 Kinase Domain: To Boldly Go Where No Immuno-Oncology Drugs Have Gone Before

“…The study also revealed that the enhanced anti-tumor activity could be further augmented by concurrent administration of anti-PD-1 antibody therapy, suggesting that the two inhibitory pathways are non-overlapping and thus could be used concurrently as dual therapy that might enhance the anti-tumor immune response additively or synergistically (Hernandez et al, 2018) (Figure 1). Taken together, these findings support previous speculation that HPK1 might be an ideal target for small-molecule-mediated inhibition that would provoke an enhanced anti-tumor immunity (Sawasdikosol et al, 2012).…”

Targeting cancer with kinase inhibitors

“…With the exception of PKA and CSK, the expression of these kinases is predominantly restricted to immune cells, suggesting selective roles in immune modulation. Accordingly, genetically engineered mouse models enabling the abrogation of PKA, CSK, MAP4K1, or DGKξ functions exhibit hallmarks of excessive immune activation and/or TCR hypersensitivity (128,(130)(131)(132) -/-mice, the role of these kinases in tumor immune surveillance has already been established, confirming the viability of these approaches for restoring antitumor immunity (131,133). In contrast, ubiquitous expression and pleiotropic functions of CSK and PKA may limit the viability of these targets in this context.…”

Towards superior dendritic-cell vaccines for cancer therapy

“…Increasing numbers of small-molecule inhibitors of suppressive signalling pathways, such as tyrosine kinase, arginase and IDO1, are being developed and used in combination with DC vaccines to alleviate tumour-related immunosuppression and to improve the immunogenicity of DC vaccines. Among these targets, HPK-1 has been identified as a novel potential druggable kinase target that could significantly improve both DC and T-cell responses in a cancer setting 44 . Moreover, PX478, an inhibitor of hypoxia inducible factor 1 α (HIF1α; a central regulator of tumour-induced hypoxia-associated immune suppression), was demonstrated to enhance the efficacy of a DC vaccine in a mouse model of breast cancer 52 .…”

“…Indoleamine 2,3-dioxygenase 1 (IDO1) was expressed at high levels on CD141 + DCs (basal and post-activation), on activated MoDCs and, to a lesser degree, on activated pDCs. Homeodomain-interacting protein kinase-1 (HPK-1), a kinase recently identified as a negative regulator of DC and T-cell function 44 , was found to be highly expressed at steady state on CD141 + DCs and was downregulated on activation. These observations suggest that the same checkpoint-blockade approach may not be optimal for all DC subsets.…”