IRF7-regulated gene expression in breast tumor cells prevents bone metastasis.
Major finding: IRF7-regulated gene expression in breast tumor cells prevents bone metastasis.
Mechanism: IRF7-mediated IFN signaling stimulates tumor immune surveillance by NK cells and T cells.
Impact: Treatment with type I IFN may reduce metastatic spread in patients with breast cancer.
Escape from immunosurveillance mechanisms that recognize and eliminate malignant cells is an important step in tumor growth and progression. To address the importance of tumor immune surveillance in metastasis, Bidwell and colleagues evaluated the gene expression profiles of murine breast cancer cells and matched bone metastases. Genes downregulated in bone metastases were enriched for IFN effector genes that are induced by IFN regulatory factor 7 (IRF7), an important mediator of type I IFN signaling. Expression of Irf7 was also reduced in metastases, and overexpression of IRF7 in breast cancer cells rescued activation of these IFN-regulated genes. Furthermore, although primary tumor growth was not affected, the formation of spinal metastases was significantly diminished by IRF7 expression. This reduction in metastasis was associated with prolonged survival and was dependent on IFN signaling, as the protective effect of IRF7 against metastasis was lost in mice deficient for IFN receptor. In addition, IRF7 did not improve metastasis-free survival in immunodeficient mice, suggesting that this effect is mediated through IFN signaling to functional immune cells. Specifically, IRF7 expression in tumors resulted in decreased myeloid-derived suppressor cells, which promote tumor growth, and elevated numbers of natural killer (NK) cells and CD8+ T cells, which are activated by IFN to facilitate tumor cell elimination. Depletion of tumor-suppressive NK cells and T cells accelerated bone metastasis, whereas treatment with IFN was sufficient to inhibit metastasis and enhance NK cell accumulation. Importantly, low expression of IRF7-regulated genes was correlated with increased bone metastasis in breast cancer patient data sets. Together, these results identify an innate immune surveillance pathway that suppresses breast cancer metastasis and suggest that type I IFNs may be clinically useful in limiting metastatic outgrowth in breast cancer.