The soluble α chain of interleukin-15 receptor:: A proinflammatory molecule associated with tumor progression in head and neck cancer

Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor alpha (TNF alpha), IL-17, etc.]. A correlation between high intratumoral IL-15 concentrations and poor clinical outcome in lung and head and neck cancer patients has been recently reported. The purpose of this study was to investigate the role of the soluble alpha chain of IL-15 receptor (sIL-15R alpha), a natural regulator of IL-15, in head and neck cancer. Fifty-three newly diagnosed untreated head and neck cancer patients were included in this study. Quantification of sIL-15R alpha was performed with a newly developed RIA. Increased serum sIL-15R alpha concentrations were found in head and neck cancer patients and were closely correlated with poor clinical outcome both in terms of locoregional control and survival even on multivariate analysis. sIL-15R alpha was mainly produced by tumor cells via proteolytic cleavage of IL-15R alpha mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15R alpha concentrations. Surprisingly, sIL-15R alpha did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15-induced proinflammatory cytokines (IL-6, TNF alpha, and IL-17) that may promote tumor progression. This new tumor evasion mechanism based on amplification of the intratumoral inflammatory reaction is probably not restricted to head and neck cancer, as other tumors have been shown to release sIL-15R alpha. Overall, these results support for the first time an original protumor role of sIL-15R alpha in cancer.