Several studies have correlated high numbers of
tumor-infiltrating natural killer (NK) cells with a good prognosis for
cancer patients. Our study aimed at identifying factors controlling intratumoral NK cell accumulation in s.c. injected NK cell sensitive
tumor models and at studying their effect on survival time of recipient mice. We observed that fewer NK cells infiltrated the
tumors in IFN-gamma receptor knockout (
IFN-gammaR(-/-)) mice compared with wild-type controls that correlated with decreased survival rate. Exogenous application of IFN-gamma in the
tumor augmented levels of
ligands of the
chemokine receptor CXCR3, increased NK cell accumulation, and prolonged survival. Furthermore, our data show that CD27(high) NK cells, which under steady-state conditions express CXCR3, preferentially accumulated in the
tumor tissue. Accordingly, significantly lower numbers of
tumor-infiltrating NK cells were detected in CXCR3(-/-) mice, and the capacity of adoptively transferred CXCR3(-/-) NK cells to accumulate in the
tumor was severely impaired. Finally, exogenous application of the CXCR3
ligand CXCL10 in the
tumor or ectopic expression of CXCL10 by
tumor cells increased the numbers of NK cells in the
tumors and prolonged NK cell-dependent survival. Our results identify IFN-gamma and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into
tumors. Exploiting strategies to augment NK cell accumulation in the
tumor might lead to the development of effective antitumor
therapies.