The combined action of IL-15 and IL-12 gene transfer can induce tumor cellrejection without T and NK cell involvement

The cooperative antitumor effects of IL-12 and IL-15 gene transfer were stu died in the N592 MHC class I-negative small cell lung cancer cell line xeno transplanted in nude mice. N592 cells engineered to secrete IL-15 displayed a significantly reduced tumor growth kinetics, and a slightly reduced tumo r take rate, while N592 engineered with IL-12 displayed only minor changes in their growth in nude mice. However, N592 cells producing both cytokines were completely rejected, and produced a potent local bystander effect, ind ucing rejection of coinjected wild-type tumor cells. N592/IL-12/IL-15 cells were completely and promptly rejected also in NK-depleted nude mice, while in granulocyte-depleted animals a slight delay in the rejection process wa s observed. Immunohistochemical analyses of the N592/IL-12/IL-15 tumor area in intact nude mice revealed the presence of infiltrating macrophages, gra nulocytes, and NK cells, and expression of inducible NO synthase and of sec ondary cytokines such as IL-1 beta, TNF-alpha, and IFN-gamma, and at higher levels GM-CSF, macrophage-inflammatory protein-2, and monocyte chemoattrac tant protein-1. In NK cell-depleted nude mice, numerous macrophages and gra nulocytes infiltrated the tumor, and a strong expression of macrophage-infl ammatory protein-2 and inducible NO synthase was also observed. Finally, ma crophages cocultured with N592/IL-12/IL-15 produced NO in vitro, and inhibi ted tumor cell growth, further suggesting their role as effector cells in t his model.