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

Abstract

Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)c. 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, IFNc 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.

Chemotherapy ± Cetuximab Modulates Peripheral Immune Responses in Metastatic Colorectal Cancer

“…Jaime-Ramirez et al [33] have shown that IL-12 enhances the antitumour actions of trastuzumab via NK cell IFN-γ production, and deficiencies in antigen presentation and IL-1 production by cancer patients' monocytes have been previously published by our group [34], as well as others [35,36]. Such abnormalities in antigen-presenting cell functions, and in particular those of reduced IL-12 and IL-18 production, further support the notion of a shift towards a Th2 type of response in cancer patients [37,38,39,40]. …”

The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

“…It was previously shown that high levels of IL-18 are present in serum and ascites of patients with EOC (12) and that pro-IL-18 is largely predominant (13). In fact, although IL-18 ELISA preferentially recognized mat-IL-18 in sera, this assay also detected pro-IL-18, albeit with a reduced sensitivity.…”

“…Some of these cytokines have been considered as serologic biomarkers of EOC (11). Among them, interleukin (IL)-18 was proposed as a potential biomarker by gene expression profiling (12) and, indeed, IL-18 levels were elevated in serum and ascites of patients with EOC (12,13).…”

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

“…Higher IL18 levels in patient plasma correlated with a longer survival time, but higher IL18 levels in cancer tissues correlated with shorter survival time. In ovarian cancer, tumor cells predominantly release the biologically inactive 24-kDa pro-IL18 (23), and only this form is detectable in the ascites of patients (24). We therefore chose an antibody specific to mature form IL18 in pancreatic cancer patients' plasma and tissues directly.…”