Cancer-induced immunosuppression: IL-18-elicited immunoablative NK cells

During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1-dependent tumor progression in NK cell-controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit ^- (CD11b ^-) into Kit ⁺natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit ⁺ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit ⁺ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1-dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18-binding protein dramatically reduced the accumulation of Kit ⁺CD11b ^- NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit ⁺CD11b ^- NK cells endowed with B7-H1-dependent immunoablative functions in mice.