Membrane-bound interleukin (IL)-15 on renal tumor cells rescues natural killer cells from IL-2 starvation-induced apoptosis

Cancer Res. 2007 Jun 15;67(12):5594-9. doi: 10.1158/0008-5472.CAN-06-4406.


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 alpha (IL-15Ralpha). Silencing of IL-15Ralpha 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-15Ralpha 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-15Ralpha 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.

MeSH terms

  • Apoptosis / physiology*
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / secondary
  • Cell Membrane / metabolism
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Interleukin-15 / metabolism*
  • Interleukin-15 Receptor alpha Subunit / metabolism
  • Interleukin-2 / metabolism*
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Killer Cells, Natural / metabolism*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / metabolism
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Microscopy, Confocal
  • RNA, Small Interfering
  • Receptor Cross-Talk / immunology
  • Reverse Transcriptase Polymerase Chain Reaction


  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Interleukin-2
  • RNA, Small Interfering