Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

Interleukin (IL)‐18 is a proinflammatory and immune‐enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL‐18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro‐IL‐18) in vitro. In addition, IL‐18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL‐18 is increased in EOC patients' sera at diagnosis as compared with age‐matched healthy women. IL‐18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL‐18 expression in cytokeratine‐positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL‐18. The detection of human IL‐18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL‐18 is tumor‐derived. However, IL‐18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL‐18 present in the ascitic fluid as pro‐IL‐18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL‐18 levels. Altogether these data indicate that IL‐18 in EOC fluids is predominantly tumor‐derived and that its lack of biological activity may represent a mechanism of tumor‐escape.