Bone metastasis is a fatal consequence of prostate cancer that can occur many years after initial primary diagnosis. This latency associated with delayed emergence in bone-avid, solid cancers is linked to dormancy, which restricts outgrowth yet facilitates tumour cell persistence. Immune regulation of dormancy has long-been been proposed. However, direct evidence to support this as a mechanism of induction and outgrowth in the osteoimmune milieu is lacking.
Utilising a membrane-labelling and single cell sequencing approach, we have recently interrogated the transcriptomes of dormant and proliferating cells in bone. Unexpectedly, our findings demonstrated that over 55% of genes lost in actively proliferating cells were interferon (IFN) regulated genes (IRGs), primarily those involved in tumour-inherent immunogenicity and immune modulation. We further demonstrated that loss of IFN pathways in active prostate cancer cells is bone-specific and inducible by a subset of immunosuppressive cells concentrated in the bone tumour microenvironment and previously linked to metastatic progression. Moreover, we confirmed loss of IRG signatures in bone metastases of prostate cancer patients. In fact, loss of core IRGs in primary tumours was associated with rapid metastasis in a large prostate cancer cohort. Additionally, we identified core IFN-associated biomarkers of skeletal modulatory processes that robustly predict biochemical recurrence in patients with early disease. Importantly, our studies have shown that accelerated metastasis to bone as a result of tumour-intrinsic IFN loss can be abrogated through epigenetic targeting and therapeutic intervention, inducing IFN-dependent T cell memory responses and innate immune activation.
Overall, these novel findings suggest that downregulation of tumour-intrinsic IFN signalling is bone specific and is a critical driver of outgrowth from dormancy. In bone, tumour-intrinsic loss of type I IFN promotes immune cell suppression and facilities tumour progression by engendering a permissive osteoimmune niche, including the induction of errant bone-remodelling. Crucially, this work demonstrates the potential of therapeutic intervention to treat or prevent bone metastasis in prostate cancer, with the aim of reducing patient mortality.