Abstract
Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of—function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.
Highlights
The splenocytes were stained with anti-B220, anti-CD3, anti-CD4, anti-CD8, anti-pan-natural killer (NK), and anti-CD11b monoclonal antibodies followed by measurement via FACS to evaluate various immune cell populations
The results revealed that various immune cell types and pathways were affected in Hematopoietic progenitor kinase 1 (HPK1) kinase dead (KD) mice, including T effector cells, dendritic cells, regulatory T cells, natural killer cells and neutrophils
The current study has demonstrated that the kinase activity of HPK1, and not the potential scaffolding function of the protein, plays a key role in the anti-tumor immune response, consistent with previous findings of HPK1 as a negative regulator of T cell receptor (TCR)-induced T-cell activation and as one of the molecules that maintain peripheral tolerance as revealed with HPK1 KO models [5]
Summary
Successful anti-tumor immunity relies on a functional “cancer-immunity cycle,” including antigen processing and presentation, activation of T cells, trafficking of antigen specific T. Studies demonstrated that mice received adoptive transfer of HPK1 KO T cells became resistant to Lewis lung carcinoma (LLC) tumor growth via mounting effective anti-tumor immune responses [7], suggesting that inhibition of HPK1 could be a viable approach for cancer immune therapy by promoting effector functions of T cells. We generated HPK1 KD mice by introducing a point mutation (Lys46Met = K46M) on the key residue responsible for HPK1 kinase activity Extensive characterization of these mice revealed a critical role of HPK1 kinase activity in mediating immune cell functions, anti-tumor immunity as well as resistance to immune suppressive factors including PGE2 and adenosine. Our data provide novel evidence that blockade of HPK1 kinase activity is sufficient to beneficial effect on enabling an optimal “cancer-immunity cycle”, supporting that pharmacological intervention of HPK1 kinase activity could serve as a novel immunomodulatory approach to anticancer therapy
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