IL-15 has innate anti-tumor activity independent of NK and CD8 T cells

IL‐15 can have innate anti‐tumor activity independent of NK and CD8+ T cells and the common gamma chain receptor. 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−/−/γc−/− 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 γcR.