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The Soluble Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

¹ EA 4054 Université Paris Descartes, Faculté de Medecine; Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France; ² Service d'Anatomie Pathologique, Hopital Européen Georges Pompidou; ³ Department of Otorhinolaryngology-Head and Neck Surgery, Hopital Européen Georges Pompidou; ⁴ Service d'Immunologie Biologique, Hopital Européen Georges Pompidou; ⁵ Centre d'Investigations Cliniques, Assistance Publique des Hopitaux de Paris; ⁶ Université Paris-Descartes, Institut National de la Sante et de la Recherche Medicale, UMR-S775; ⁷ Service d'Anatomie Pathologique, Institut Curie, Paris, France; and ⁸ Institut National de la Sante et de la Recherche Medicale, UMR 892, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes, France

Requests for reprints: Eric Tartour, Hopital Européen Georges Pompidou, Unité d'Immunologie Biologique, 20 Rue Leblanc, 75908 Paris Cedex 15, France. Phone: 33-1-56-09-39-42; Fax: 33-1-56-09-20-80; E-mail: eric.tartour{at}egp.aphp.fr.

Key Words: Soluble IL-15 receptor • Cytokine • Inflammation

Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor (TNF), 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 chain of IL-15 receptor (sIL-15R), 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 was performed with a newly developed RIA. Increased serum sIL-15R 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 was mainly produced by tumor cells via proteolytic cleavage of IL-15R mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15R concentrations. Surprisingly, sIL-15R did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15–induced proinflammatory cytokines (IL-6, TNF, 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. Overall, these results support for the first time an original protumor role of sIL-15R in cancer. [Cancer Res 2008;68(10):3907–14]

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