Data from 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. Cancer Res; 72(11); 2757–67. ©2012 AACR.