Natural killer cells inhibit breast cancer cell invasion through downregulation of urokinase-type plasminogen activator

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive types of breast cancer, and there is no effective therapeutic target to date. Natural killer (NK) cells are func- tionally diverse lymphocytes that recognize and kill cancer cells. Although it is clear that NK cells exert antitumor activity in the tumor microenvironment, their role in the aggressive progression of TNBC has not been elucidated in detail. In the present study, we investigated the effect of NK cells on MDA-MB-231 TNBC cells using an indirect co-culture system. The invasive phenotype of MDA-MB-231 cells was significantly inhibited by co-culture with NK cells. Notably, the expression of urokinase-type plasminogen activator (uPA) was markedly reduced by NK cells. Cytokine array analysis showed that the levels of interleukin (IL)-10, IL-6, IL-8, C-C motif ligand (CCL)5, and CCL2 were increased in conditioned media from the co-cultured cells. Among these cytokines, IL-6 played a crucial role in the NK cell-induced uPA downregulation and inhibition of the invasive phenotype of MDA-MB-231 cells and Hs578T cells. We analyzed the Gene Expression Profiling Interactive Analysis database for correla- tions between IL-6 and uPA with the overall survival of breast cancer patients. The Kaplan-Meier survival analysis revealed that a low IL-6/uPA ratio was associated with the poor survival of breast cancer patients, suggesting it as an important factor for determining the overall survival of breast cancer patients. Taken together, our findings demonstrate that NK cells in the tumor microenvironment inhibit the invasiveness of TNBC cells through the IL-6-mediated inhibition of uPA.