Interleukin-1ß / Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer – An Exploratory Analysis of Clinical and Tumor Biological Significance

Background: Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC) and inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1ß and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. Design, Setting, and Participants: The study included two independent cohorts of n=92 and n=102 patients who underwent radical cystectomy for BC. Specimen from BC and benign urothelium (n=22 and n=39) were processed to a tissue microarray and immunohistochemically stained for IL-1ß, IL-1RA, AKT and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. Outcome measurements and statistical analysis: Association with outcome was assessed using Wilcoxon Kruskal-Wallis tests, Chi-square tests or linear regression, dependent on the variable’s category. Kaplan–Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Results: Both, IL-1ß and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p<0.005). IL-1ß was associated with vascular invasion (210 vs. 183, p<0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). Survival analysis revealed favorable RFS, CSS, and OS in case of high IL-1ß expression (p<0.02, <0.03 and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1ß expression on RFS, CSS and OS. IL-1ß and IL-1ß/IL-1RA ratio were positively correlated to AKT expression (p<0.05 and <0.01, respectively). Additionally, high expression of Ki-67 (>15%) correlated with higher levels of IL-1β (p=0.01). Conclusions: Overexpression of IL-1ß and IL-1RA is frequently found in BC, with a prognostic significance observed for IL-1ß protein expression. The observed link between the IL-1ß / IL-1RA axis and AKT signaling may indicate possible autophagy activation processes beside the known tumor-promoting effects of AKT.