Targeting Siglec-engaging immunosuppressive sialoglycans to suppress prostate cancer bone metastasis

BACKGROUND: Prostate cancer is a leading cause of male cancer-related deaths over the age of 50. New treatment options are urgently needed, especially for prostate tumours that have spread to bone. Targeting aberrant sialylation holds substantial potential for the development of new therapeutics but is relatively unexplored in the context of prostate cancer. METHODS: Here, using high-affinity Siglec-based sialoglycan-binding reagents (HYDRA) for immunohistochemistry, we quantify tumour sialoglycans in tissues representing the full clinical heterogeneity of prostate cancer. Using immunofluorescence, we profile Siglec receptors in prostate tumours, and using syngeneic mouse models, we evaluate an engineered dual-action sialidase (E-612) as a treatment for prostate cancer bone metastasis. RESULTS: We find that sialoglycans that can engage Siglec-3 (CD33), Siglec-7 and Siglec-9 are upregulated in bone metastatic prostate cancer and show that sialoglycan ligands for Siglec-7 and -9 correlate with poorer patient prognosis. Furthermore, we reveal Siglec receptors and Siglec ligands are co-expressed by immune cells in prostate-derived tumours growing in bone. Indicating the Siglec-sialoglycan axis is clinically actionable in prostate cancer, we show systemic therapy with E-612 can suppress the growth of tumours, increase immune cell infiltration and prolong survival times of mice with bone metastasis. CONCLUSIONS: Our findings identify a novel mechanism involving Siglec-engaging sialoglycans in driving the growth of prostate cancer bone metastasis and demonstrate that targeting this axis using an engineered sialidase can impede lethal prostate cancer progression.