Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of less than 10%. One of the biggest challenges of treating pancreatic cancer is the poor response of tumours to therapy. This is largely due a dense desmoplastic (fibrotic) tumour microenvironment characterized by an abundance of immunosuppressive myeloid cells and cancer-associated fibroblasts, which collectively promote the exclusion and inactivation of cytotoxic effector cells. Thus, therapies that can simultaneously activate anti-tumour immunity and relieve immune-suppression represent promising adjuvant strategies to control PDAC development and metastasis with chemo- or immunotherapy.
Aberrant activation of the myeloid-specific kinase Hematopoietic Cell Kinase (HCK) is observed in PDAC, and correlates with poor patient survival. Using two clinically-relevant models, we demonstrate that inhibition of HCK activity impairs pancreatic tumour growth and metastasis by inducing an immune-stimulatory endotype in dendritic cells and macrophages. In turn, this enhances the infiltration and activation of CD8 T-cells and NK cells into tumours, and reduces the desmoplastic microenvironment. Accordingly, genetic ablation of HCK in murine hosts maximizes the therapeutic efficacy of chemotherapy and overcomes resistance to immunotherapy, culminating in substantially extended progression-free survival. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts also reduces tumor immunosuppression, improves T-cell recruitment, and impairs tumor growth.
Collectively, our results demonstrate that targeting HCK can overcome barriers that limit anti-tumour responses to therapy, and provide a compelling rationale for HCK as a tyrosine kinase drug target to improve the responsiveness of PDAC to chemotherapy and/or immune checkpoint blockade.