Natural killer cell cytotoxicity receptor 3 ligand 1 (B7-H6) (B7-H6)

Natural killer cell cytotoxicity receptor 3 ligand 1, commonly known as B7-H6, is a member of the B7 family of immune checkpoint molecules. Unlike many other B7 family members that are widely expressed, B7-H6 is notably absent from most healthy adult tissues but is highly upregulated on the surface of various primary tumors and cancer cell lines (Brandt et al., 2009, J Exp Med). Its primary biological role is to serve as a potent ligand for NKp30, an activating receptor expressed on natural killer (NK) cells, thereby triggering NK cell-mediated cytotoxicity and cytokine production. In the context of malignancy, B7-H6 expression allows the immune system to identify and eliminate transformed cells; however, tumors often employ mechanisms such as metalloprotease-mediated shedding of B7-H6 to create a soluble decoy (sB7-H6) that inhibits NK cell function and promotes immune evasion (Schlecker et al., 2011, Cancer Res). Because of its tumor-restricted expression pattern, B7-H6 is an attractive target for various cancer immunotherapies, including bispecific T-cell engagers (BiTEs), bispecific killer cell engagers (BiKEs), and chimeric antigen receptor (CAR) T-cell therapies. For example, the bispecific antibody BI 765049 is designed to redirect T cells to B7-H6-positive tumor cells (ClinicalTrials.gov: NCT04430829). These treatments aim to harness the cytotoxic activity of the immune system specifically against B7-H6-expressing malignancies while minimizing damage to healthy tissues. Current research focuses on overcoming the inhibitory effects of soluble B7-H6 and enhancing the persistence of B7-H6-targeted effectors within the tumor microenvironment.

Other names

NCR3LG1B7H6B7 homolog 6Natural killer cell cytotoxicity receptor 3 ligand 1

B7-H6 acts as a ligand for the activating receptor NKp30 (NCR3) on natural killer (NK) cells. Therapeutic strategies include bispecific antibodies (e.g., BiTEs or BiKEs) that bridge B7-H6 on tumor cells with CD3 on T cells or CD16/NKp46 on NK cells to induce targeted cell lysis (Schierbeck et al., 2020, Front Immunol). Additionally, CAR-T cells are engineered to express receptors that directly recognize B7-H6 on the tumor surface (Wu et al., 2015, Gene Ther).