Uveal melanoma (UM) is the most common intraocular
tumor in adults and liver
metastasis is the leading cause of death in UM patients. We have previously shown that NKT cell-deficient mice develop significantly fewer liver
metastases from intraocular
melanomas than do wild-type (WT) mice. Here, we examine the interplay between liver NKT cells and NK cells in resistance to liver
metastases from intraocular
melanomas. NKT cell-deficient CD1d(-/-) mice and WT C57BL/6 mice treated with anti-CD1d antibody developed significantly fewer liver
metastases than WT mice following either intraocular or intrasplenic injection of B16LS9
melanoma cells. The increased number of
metastases in WT mice was associated with reduced liver NK cytotoxicity and decreased production of IFN-γ. However, liver NK cell-mediated cytotoxic activity was identical in non-
tumor bearing NKT cell-deficient mice and WT mice, indicating that liver
metastases were crucial for the suppression of liver NK cells. Depressed liver NK cytotoxicity in WT mice was associated with production of
IL-10 by bone marrow-derived liver cells that were neither Kupffer cells nor myeloid-derived suppressor cells and by increased
IL-10 receptor expression on liver NK cells. IL-10(-/-) mice had significantly fewer liver
metastases than WT mice, but were not significantly different from NKT cell-deficient mice. Thus, development of
melanoma liver
metastases is associated with upregulation of
IL-10 in the liver and an elevated expression of
IL-10 receptor on liver NK cells. This impairment of liver NK activity is NKT cell-dependent and only occurs in hosts with
melanoma liver
metastases.