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Membrane-Bound Interleukin (IL)-15 on Renal Tumor Cells Rescues Natural Killer Cells from IL-2 Starvation-Induced Apoptosis

¹ Institut National de la Santé et de la Recherche Médicale U753; ² Institut National de la Santé et de la Recherche Médicale U542, Hôpital Paul Brousse; ³ Centre National de la Recherche Scientifique UMR 8121, Laboratoire de Vectorologie et Transfert de Genes; ⁴ Unité des Thérapies Innovantes, Institut Gustave Roussy, Villejuif, France and ⁵ Institut Mutualiste Montsouris, Paris, France

Requests for reprints: Anne Caignard, Unite Institut National de la Santé et de la Recherche Médicale U753 "Immunologie des Tumeurs humaines: interactions effecteurs cytotoxiques-système tumoral" Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42-11-50-36; Fax: 33-1-42-11-52-88; E-mail: caignard{at}igr.fr.

Renal cell carcinoma primary tumors and lung metastases are infiltrated by activated natural killer (NK) cells. Interleukin (IL)-15, a major cytokine involved in cross-talk between accessory cells (dendritic cells and macrophages) and NK cells, is produced by epithelial renal cells. We show that renal cell carcinoma cells and normal renal cells express IL-15 mRNA and membrane-bound IL-15 (MbIL-15). These cells also express IL-15 receptor (IL-15R). Silencing of IL-15R by specific small interfering RNA in renal cell carcinoma had no effect on MbIL-15 production, indicating that the cytokine is not cross-presented by IL-15R in renal cell carcinoma cells but anchored to the membrane. Furthermore, we show that MbIL-15 from renal cell carcinoma cells is functional and involved in rapid nuclear translocation of phosphorylated signal transducers and activators of transcription 3 in IL-2–starved NK cells. MbIL-15 on the target did not interfere with resting NK cell activation and target cell cytolysis but rescued NK cells from IL-2 starvation-induced apoptosis through contact-dependent interaction. Masking of MbIL-15 with soluble IL-15R molecules restored NK cell apoptosis. These findings suggest that IL-15 produced by renal tumor cells is involved in the maintenance of active NK cells at the tumor site. [Cancer Res 2007;67(12):5594–9]

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