Prostate cancer is the most common non-skin cancer in males, with 1 in 5 men developing the disease in their lifetime. Due to early diagnosis and treatment, the average 5 year survival rate for men diagnosed with prostate cancer is 90%. Nevertheless, after successful surgery and treatment, 10% of prostate cancer patients develop progressive metastatic disease and at least 90% of these advanced patients have bone involvement.
To date, the mechanisms driving bone-specific spread and selective tumour growth in the bone microenvironment are still poorly understood. We have utilised an immunocompetent mouse model of prostate cancer incorporating cell lines that weakly (RM9) or aggressively (RM1) metastasise to bone to explore the role of immune regulation in bone metastasis. In vitro analysis of RM1 and RM9 cells revealed a comparable susceptibility to NK cell mediated killing. However, contact of RM1 cells with NK cells resulted in tumour cell secretion of substantial amounts of the anti-inflammatory cytokine IL-10, and the chemokines CCL2 and CCL5. This was specific to the aggressive cell line, as co-culture of NK cells with the weakly metastatic RM9 cells had reduced or absent CCL5 and IL-10 secretion, respectively.
After intracardiac injection into C57 Bl/6 mice, RM9 cells significantly increased the proportion of activated and functional IFN-γ+ NK cells in the peripheral blood compared to RM1 cells. Importantly, NK depletion led to a dramatic increase of RM9-induced bone metastasis, indicating a substantial role of NK cells for the progression of prostate cancer metastasis to bone in this model. In contrast, mice bearing the highly metastatic RM1 line accumulated increased peripheral regulatory T-cells, suggesting distinct immune stimulatory potentials of the two different tumour cells lines, with RM9 cells inducing immune activation and RM1 cells inducing an immune suppressed state.
Our study suggests that tumour-cell specific cytokine signalling contributes to the development of bone metastasis by effecting the development of an immune response during prostate cancer.