Identifying ligands for the activating NK cell receptor NKp46

Natural killer (NK) cells are innate effector cells that participate in defense against viral infections and malignancies. The cytotoxicity of NK cells is regulated by a battery of activating and inhibitory receptors. Among these, the activating receptor NKp46 is pivotally involved in NK cell recognition of multiple cancer cell types.

Despite the key role of NKp46, its cognate ligand expressed by cancer cells has hitherto evaded identification.

We have genetically engineered target cells to be recognized predominantly via NKp46 and exposed these cells to NK cells in genome-wide CRISPR screens to identify NKp46 ligand candidates.

Our preliminary results strongly suggest that we have indeed identified new ligands to NKp46, and this research program comprises an ambitious multidisciplinary effort to determine how NKp46 interacts with these ligands and other structures in cis and trans in the immunological synapse.

We will delineate how the ER stress response and the UFMylation pathway are associated with the cell surface expression of these ligands and use animal studies to test the relevance of these findings in vivo.

Finally, we will investigate if the discovery of these ligands can be exploited therapeutically as multifunctional engagers or chimeric antigen receptors.