Role of CXCR3 in natural killer cell migration to melanoma cells

Abstract

Abstract Natural killer (NK) cell recruitment to solid tumors is essential for direct contact between NK and cancer cells and is regulated by chemokine networks. Tumor-derived CXCL10 increases the infiltration of NK cells into solid tumors. In a xenograft mouse model, adoptively transferred human NK cells efficiently infiltrate CXCL10-transduced tumors and enhance regression of tumor growth compared with mock-transduced tumors. Although this study showed that NK cells homed to solid tumor beds in a CXCL10-depedent manner, several questions remain. How do NK cells find cancer cells after extravasation? Which chemokines do B16F10 cells produce? Which chemokine receptors do NK cells use? How do cancer cell-derived chemokines affect NK cell motility? Do these chemokines directly affect NK cell cytotoxicity? To address these issues, we examined the migration dynamics of NK and cancer cells using time-lapse imaging. Although naïve B16F10 cancer cells produce low levels of chemokines, IFN-g-treated B16F10 cells secreted high levels of CXCL10, low levels of CCL5, but did not secrete CCL2, CCL7, or CXCL12. Wild-type NK cells migrated well toward cancer cells and killed them, whereas NK cells deficient in CXCR3 did not. CXCR3-deficient NK cells also showed slower migration speed than did wild-type NK cells. Taken together, our data show that NK cells find cancer cells, at least in part, by sensing CXCL10 produced by cancer cells and suggest that a strategy to increase CXCL10 secretion by cancer cells may improve the efficacy of NK cell–based immunotherapy.