IL-15 has innate anti-tumor activity independent of NK and CD8 T cells.
The innate immune system is crucial for host defense and immunosurveillance against pathogens and tumor cells. IL-15 is a pleiotropic cytokine with important effects on cells of the innate and adaptive immune systems. The NK cell- and CD8(+) T cell-mediated functions of IL-15 against tumor cells have been well documented. However, it has not been established whether IL-15 has innate anti-tumor functions independent of these cells. Here, we explored the innate anti-tumor potential of IL-15 using a B16F10 melanoma tumor model. IL-15tg mice exhibited significantly more resistance to tumor growth and metastasis compared to B6 mice, and to IL-15(-/-) mice, which exhibited increased susceptibility to B16F10 challenge. In vivo depletion of NK cells and CD8(+) T cells abrogated the innate resistance to B16F10 cells in B6 but not in IL-15tg mice. In addition, lung macrophages from IL-15tg mice produced significantly higher levels of NO and IL-12 compared with macrophages from B6 or IL-15(-/-) mice. To examine whether IL-15 has innate anti-tumor activity independent of NK cells and CD8(+) T cells, we developed Ad-Op-hIL-15; this resulted in significantly higher levels of biologically active hIL-15. Delivery of Ad-Op-hIL-15 into RAG-2(-/-)/gamma(c)(-/-) mice significantly suppressed tumor burden in the lungs compared with the control adenovirus vector. Our results show that IL-15 can have innate anti-tumor activity independent of NK cells and CD8(+) T cells and the common gamma(c)R.
Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada L8N 3Z5.
Elizabeth
E
Davies
Sarah
S
Reid
Maria Fe
MF
Medina
Brian
B
Lichty
Ali A
AA
Ashkar
D056704:Adaptive Immunity / Q000276:immunology; D000256:Adenoviridae; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002452:Cell Count; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007142:Immunoglobulin gamma-Chains / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D010641:Phenotype; D015398:Signal Transduction / Q000276:immunology
D004268:DNA-Binding Proteins; D007142:Immunoglobulin gamma-Chains; D019409:Interleukin-15; C499308:Rag2 protein, mouse; D018664:Interleukin-12; D009569:Nitric Oxide