A double-edged sword - the role of human ADAM17 in NK cell activity

ADAM17 is a pleiotropic sheddase that regulates the activity of diverse membrane-anchored proteins by proteolytic cleavage. Also, many immune functions depend on ADAM17 activity, for instance CD16 and TNFα, two key effector molecules of Natural Killer cells, are cleaved by this enzyme. Whereas CD16 is shed from the surface and therefore its activity is terminated by ADAM17, TNFα requires shedding to be soluble and fulfil its effector functions. Due to these antagonistic effects on immune system activity, clinical benefits of ADAM17 inhibition for the treatment of cancer patients are hard to predict. Recently, we reported of a patient with a very rare genetic deficiency of ADAM17 leading to a complete loss of ADAM17 protein. We characterized the patient’s PBMCs for cytokine secretion in response to LPS stimulation, as well as for antibody-dependent cellular cytotoxicity (ADCC) effector functions and IFNγ release following engagement of CD16. In this short review, we highlight these recent findings and discuss putative consequences for the clinical use of inhibitors for ADAM17.