NKp30 and its ligands: emerging players in tumor immune evasion from natural killer cells

It is indisputable that natural killer (NK) immune surveillance is of crucial importance for hematological and solid tumors. However, the outcome of NK cell-based immune therapies appears disappointing in many trials. Limitations include poor in vivo survival or lack of specificity and are often attributed to tumor-associated immune escape mechanisms. NK cells are terminally activated by ligation of the activating NK receptors NKG2D, NKp30 or NKp46 through their corresponding ligands, which are up-regulated on the cell surface of dangerous cells (1-5). There is evidence that malignant cells bypass the NK surveillance by releasing these ligands as soluble proteins, as shown for NKG2D and NKp30 ligands (6-10). In most cases, the ligands are released by metalloproteinase-dependent shedding. The relevance of this mechanism was clearly confirmed in a transgenic animal model, showing spontaneous growth of tumors with the shedding-proficient NKG2D ligand MICA but tumor-free survival of animals with a shedding-resistant NKG2D ligand (11).