High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer and has shown limited response to immune checkpoint blockade (ICB), which is thought to arise from a myeloid cell-orchestrated immune-suppressive tumour microenvironment. We have recently shown that ablation of the cytosolic tyrosine kinase HCK, which is expressed in tumour-associated myeloid cells, converts immune-suppressive to immune-permissive tumour microenvironment and confers effectiveness of ICB therapy to otherwise unresponsive pancreatic cancer in mouse models.
Here, we test the hypothesis that HCK may also be a therapeutically targetable signaling node that limits ICB-response of HGSOC by using p53/Brca2 syngeneic cell model in immune competent hosts. We observe significantly reduction in ascites formation and tumour burden in host which genetically lack HCK expression, and this is associated with reduced tumour cell proliferation and enhanced recruitment and activation of CD8+ T- and NK- effector cells. These findings coincide with increased expression of immune-activating factors and decreased expression of immunosuppressive markers, alongside reduced proportions of immunosuppressive CD206+ macrophages and myeloid derived suppressor cells. Importantly, in HCK-deficient hosts we find improved anti-PD1 responses of HSGSOC tumours and associated ascites accumulation. These observations can be partially replicated by therapeutic administration of the tool compound RK20449, with known activity against HCK and the related T-cell receptor-associated LCK kinase.
We are currently developing novel small molecule inhibitors with increased affinity to HCK over LCK using biochemical and cellular assay. For the latter, we have substituted the growth factor-dependency of BaF0/3 cells by selective expression of constitutive active isoforms of HCK either LCK, in order to use selective inhibition of proliferation for the functional assessment of specificity of candidate inhibitor molecules.