IL-18-Primed Helper NK Cells Collaborate with Dendritic Cells to Promote Recruitment of Effector CD8+ T Cells to the Tumor Microenvironment

Chemokine-driven interactions of immune cells are essential for effective antitumor immunity. Human natural killer (NK) cells can be primed by the interleukin (IL)-1-related proinflammatory cytokine IL-18 for unique helper activity, which promotes dendritic cell (DC) activation and DC-mediated induction of type-1 immune responses against cancer. Here, we show that such IL-18-primed helper NK cells produce high levels of the immature DC (iDC)-attracting chemokines CCL3 and CCL4 upon exposure to tumor cells or the additional inflammatory signals IFN-alpha, IL-15, IL-12, or IL-2. These helper NK cells potently attract iDCs in a CCR5-dependent mechanism and induce high DC production of CXCR3 and CCR5 ligands (CXCL9, CXCL10, and CCL5), facilitating the subsequent recruitment of type-1 effector CD8(+) T (T-eff) cells. Using cells isolated from the malignant ascites of patients with advanced ovarian cancer, we show that helper NK cell-inducing factors can be used to enhance local production of T-eff cell-recruiting chemokines. Our findings reveal the unique chemokine expression profile of helper NK cells and highlight the potential for using two-signal-activated NK cells to promote homing of type-1 immune effectors to the human tumor environment. (C)2013 AACR.