The Regulatory Effect of UL-16 Binding Protein-3 Expression on the Cytotoxicity of NK Cells in Cancer Patients

The activating immunoreceptor NKG2D (natural killer group 2, member D) and its ligands play important roles in the innate and adaptive immune responses. UL16-binding protein 3 (ULBP3), an NKG2D ligand, is overexpressed on certain epithelial tumor cells. In this study, we investigated the effect of ULBP3 expression on the cytotoxic activity of natural killer (NK) cells. ULBP3 were measured by flow cytometry analysis, immunohistochemistry, and time-resolved fluoroimmunoassay. The cytotoxicity of NK cells was determined with the lactate dehydrogenase release assay. We found that ULBP3 was overexpressed on tumor cell lines and tumor tissues. Serum from cancer patients, but not from healthy donors, contained elevated levels of soluble ULBP3 (sULBP3). Importantly, high expression of ULBP3 on the cell surface of tumor cells augmented NKG2D-mediated NK cell cytotoxicity. However, low levels of sULBP3 (<15 ng/ml) weakened the cytotoxicity of NK cells by decreasing NKG2D expression on NK cells. Further analysis showed that serum samples from most cancer patients (>70%) contained the low level of sULBP3. Our results demonstrate that tumor cells express surface and soluble ULBP3, which regulate NK cell activity. Thus, ULBP3 is a potential therapeutic target for improving the immune response against cancer.