Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8(+) T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis-free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.

The innate immune system senses pathogens by pattern recognition receptors (PRR) that signal to induce effector cytokines, such as type I interferons (IFNs). We characterized IFNε as a type I IFN because it signaled via the Ifnar1 and Ifnar2 receptors to induce IFN-regulated genes. In contrast to other type I IFNs, IFNε was not induced by known PRR pathways, but was instead constitutively expressed by epithelial cells of the female reproductive tract (FRT) and hormonally regulated. Ifnε-deficient mice had increased susceptibility to infection of the FRT by common sexually transmitted infections (STIs) Herpes Simplex Virus (HSV)-2 and Chlamydia muridarum. IFNε is thus a potent anti-pathogen and immunoregulatory cytokine that may be important in combating STIs which represent a major global health and socioeconomic burden.

The interferons (IFNs) were originally described over 50 years ago, identified by their ability to confer viral resistance to cells. We now know that they are much more than just anti-viral cytokines collectively having roles in both innate and adaptive immune responses, in tumor surveillance and defense, and modulation of immune cell function. Three types of IFN have now been described, simply referred to as type I, II and III. Distinguishable by the unique receptors that they rely on for signal transduction, the three types of IFN have specific and varied roles in the maintenance of human health and defense against pathogens. In mounting an IFN-mediated immune response, the human body has developed the ability to regulate IFN-mediated signal transduction. Like all cytokines, the ability of a cell to respond to IFN is completely dependent on the presence of its cognate receptor on the surface of the target cell. Thus, one of the major mechanisms used by the human body to regulate the strength and duration of the IFN response is through regulation of receptor levels, thereby altering the cytokine-specific responsiveness of the target cell. This review will discuss the receptor system utilized by the type I IFNs and compare it with that of the type II and III IFNs, which also regulate immune responses through controlling receptor level on the cell surface. Keywords: interferon signaling; receptors; regulation Discovered over 50 years ago, the interferons (IFNs) were first identified and are historically best known for their ability to elicit viral resistance to cells. 1 On the basis of this criteria the IFNs were initially classified into two types-the type I family composed of the acid-stable forms IFNa and IFNb, whereas the acid-labile form, IFNg, was classified as the lone type II IFN. 2 In recent years, a third type of IFN has been described, IFNl. 3 Originally termed interleukin (IL)-28a/b and IL-29 these proteins have been re-classified as IFNs based on the similar modes of induction and anti-viral activities they share with the type I and type II IFNs. 3 However, although the type I and type III IFNs are induced during a viral infection and are, at least in part, involved in host defense against viruses, the type II IFN is primarily involved in the allergic response, in host defense against intracellular pathogens and in control of tumors.The cytokines that make up the three types of IFNs share basic secondary structural elements with an overall five helical bundle architecture. The IFNs are all classified as class II alpha-helical cytokines and thus in the same protein family as IL-10, But besides a conserved overall helical-bundle fold, the IFNs otherwise share very limited homology, undoubtedly reflected by their use of distinct receptors for signal transduction. There are nine identified mammalian type I IFN subtypes including IFN-a, of which there are 13 known subtypes, and single forms of IFN-b, IFN-e, IFN-k, IFN-o, IFN-d, IFN-t, IFN-v, IFN -z. 4 These cytokines can share as much as 100% homology ...