Bone metastases are characteristic of prostate cancer in up to 90% of men who develop treatment-refractory disease, which invariably leads to death within 12-24 months of detection. Immune surveillance mechanisms associated with the regulation of cancer progression in bone have long-been proposed. However, evidence to support tumour-induced alterations in immune signalling as a means of bone-metastatic outgrowth is lacking.
We have recently revealed that over 55% of genes lost in prostate cancer cells in bone metastases are interferon (IFN) regulated genes, primarily those involved in lymphocyte activation and tumour immunogenicity. We demonstrated that tumour-intrinsic loss of type I IFN and downstream targets is bone specific and inducible by contact-dependent interactions with bone marrow cells, highlighting the importance of the microenvironment in tumour-driven immune escape. Biologically altered tumour-cell IFN dictated the temporal development of bone metastases and molecular restoration of IFN in bone-derived tumour cells with pathway loss abrogated bone metastases formation, decreased bone cell activation and promoted T cell function. Importantly, tumour-intrinsic IFN suppression could be therapeutically reversed through epigenetic targeting. In combination with an immune-activatory agent, a class-specific HDAC inhibitor was sufficient to block tumour growth in bone. Decreased metastasis was linked to tumour-intrinsic IFN-dependent upregulation of immunogenicity markers and a robust memory T cell response. Findings were validated in four independent prostate cancer cohorts, in which we demonstrated that loss of IFN in bone-metastatic lesions was indeed intratumoural compared to matched primary tumours, resulted in widespread HLA suppression, and significantly predicted biochemical recurrence.
Our findings suggest that downregulation of tumour-intrinsic IFN is a critical driver of prostate cancer progression in bone. Given that tumour-intrinsic IFN loss is associated with decreased tumour immunogenicity, this may help explain the failure of current immune-based therapies to alter survival outcomes for men harbouring castrate-resistant bone-metastatic disease. Here we highlight the potential of therapeutic intervention in a castrate-resistant setting and encourage more systematic trials targeting tumour-inherent immune signalling in prostate cancer patients.