Squamous cell carcinoma cells differentially stimulate NK cell effector functions: The role of IL-18

Tumor cells stimulate natural killer (NK) cell effector functions, but the regulation of cytokine secretion and cytolysis is incompletely understood. We tested whether oral and pharyngeal squamous cell carcinoma cell lines differentially stimulated NK cell interferon-γ (IFN-γ) secretion and cytolysis using a clone of the NK-92-transformed human NK cell line, NK92.35. SCC-4 and SCC-25 cells, but not FaDu or Cal 27 cells, stimulated robust NK92.35 IFN-γ secretion. All four carcinoma cell lines were lysed by NK92.35 cells. These findings indicate that carcinoma cells differentially stimulate NK cell IFN-γ secretion and cytolysis. In Transwell experiments, a combination of SCC-4 or SCC-25 cell soluble factors and contact with FaDu cells synergistically stimulated NK92.35 cell IFN-γ secretion. Stimulatory SCC-4 cells constitutively secreted IL-18, a cytokine that potently augments IFN-γ secretion by T cells and NK cells. In contrast, poorly stimulatory FaDu cells produced little or no IL-18, but synergized with recombinant IL-18 to stimulate NK92.35 IFN-γ secretion. mAb to IL-18 or IL-18 receptor diminished SCC-4-stimulated IFN-γ secretion by NK92.35 cells and by nontransformed NK cells. Thus, IL-18 was necessary for optimal carcinoma stimulation of NK cell IFN-γ secretion. In vivo, oral and upper aerodigestive tract epithelia and carcinomas produced IL-18, but one squamous cell carcinoma had heterogeneous IL-18 expression. Thus IL-18 production can account for squamous cell carcinoma differential stimulation of NK cell effector functions in vitro and may be important for stimulation of NK cells in vivo.