Elevated expression of the myeloid cell-specific Src-family kinase HCK occurs in a majority of solid malignancies and correlates with poor patient survival [Poh et al., Frontiers Oncol 2018]. We have recently shown that genetic ablation, or therapeutic inhibition, of HCK suppresses the growth of primary tumours arising in the colon, stomach, lung and other mutagenized epithelia of mice. Mechanistically, we have attributed this to the capacity of HCK activity to support and retain the polarization of a wound-healing, Tie2+ (i.e. alternative activated) endotype of tumour-associated macrophages and concomitant tumour vascularization [Poh et al., Cancer Cell 2017].
Here we extend these observations to a pancreatic allograft cancer model, where the growth of the primary lesion and its metastatic spread is suppressed in HCK knockout hosts. More importantly, HCK gene deletion or therapeutic HCK inhibition in mouse models of gastrointestinal cancers or melanoma further enhances the anti-tumour effects conferred by single agent immunotherapies with anti-PD-L1, anti-CTLA4 or agonistic-CD40 antibodies. The latter observations are underpinned by increased tumour cell apoptosis, which coincides enhanced expression of ifng, gzmb, prf1 and other effector proteins in NK and infiltrating CD8+ cells as well as increased expression of il12 and ifng in tumour-associated macrophages, which adopt a more conventional activated endotype. Because HCK-deficiency of the host also associated with increased abundance of tumour infiltrating effectors cells, we propose that therapeutic targeting of HCK not only “makes tumours hotter”, but also improves host anti-tumour immunity. We are therefore developing novel HCK-specific small molecule inhibitors.