Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30

Natural killer (NK) cells are powerful immune effectors that play a crucial role in antitumor immunity. However, during immunoediting, tumor cells develop mechanisms to evade NK-cell recognition. In this study, we identify a novel immune escape strategy involving the shedding of B7-H6, a ligand for the activating NK receptor NKp30, which is essential for NK-cell binding and cytotoxic activity. Tumor cells from various cancer types released B7-H6 through ectodomain shedding, mediated by the cell surface proteases ADAM10 and ADAM17, as demonstrated using pharmacologic inhibitors and siRNA-mediated gene silencing. Blocking this proteolytic process increased Marimastat B7-H6 expression on the tumor cell surface, thereby enhancing NKp30-dependent NK-cell activation. Notably, we detected elevated soluble B7-H6 levels in the blood sera of patients with malignant melanoma compared to healthy controls, alongside increased B7-H6 expression in melanoma tissue specimens. Collectively, our findings reveal a previously unrecognized immune evasion mechanism in which tumor cells escape NK-mediated recognition via metalloprotease-driven B7-H6 shedding. These results suggest that targeting specific metalloproteases could enhance NK-cell-based cancer therapies.