Interleukin (IL)-15 superagonist mediates immunotoxicity by inducing hyperproliferation of activated NK cells and production of IFNγ

Abstract

Abstract Interleukin (IL)-15 is currently undergoing clinical trials to assess its anti-tumor efficacy. IL-15 is essential for the generation, function and survival of natural killer (NK), natural killer T (NKT) and memory phenotype (MP) CD8+T cells. The combination of IL-15 with its soluble IL-15 receptor α (IL-15Rα) generates a complex termed IL-15 superagonist (IL-15 SA) that exhibits more profound biological activities on NK, NKT and MP CD8+T cells than IL-15 alone. Thus, IL-15 SA is a potentially more attractive therapeutic agent for use against advanced tumors. However, the safety of IL-15 SA administration in vivo is not clearly elucidated. This study was designed to evaluate toxic consequences of IL-15 SA in mice. Administration of 2 μg IL-15 SA for 4 days caused a time- and dose-dependent immune-toxicity, characterized by hypothermia, weight loss, liver damage and death. At 2ug, IL-15 SA expanded NK cells in spleens and livers compared to vehicle and significantly increased NK cell expression of CD69, NKG2D and NKp46 as well as production of IFNγ, granzyme B and perforin. IL-15 SA also prompted NK cell maturity with a preferential expansion of the pro-inflammatory (CD27+ CD11b+) NK subset. Mice depleted of NK cells by anti-asialoGM1or anti-NK1.1 were resistant to IL-15 SA-induced toxicity, whereas adoptive transfer of wild type NK cells to Rag2−/−γc−/− mice re-established IL-15 SA toxicity. While IL-15 SA expanded NKT and mCD8+ T cells, mice depleted of NKT or CD8+ T cells remained sensitive to IL-15 SA-mediated toxicity. In addition, IFNγ KO, but not TNF-α KO or perforin KO, mice were resistant to IL-15 SA-induced toxicity. In conclusion, high-dose IL-15 SA causes systemic immunotoxicity via induction of NK cell proliferation and activation.