Insights into ectodomain shedding as a novel target in natural killer cell-based immunotherapy for cancer

Natural killer (NK) cells are innate lymphocytes that kill cancer cells and produce cytokines/chemokines that drive anti-tumor immune responses. NK cells are controlled by activating and inhibitory receptors, of which some, or their ligands, are regulated by ectodomain shedding, which is a post-translational modification to transform surface proteins into soluble peptides. Although ectodomain shedding is essential for normal development and physiology, it is also an immune suppression mechanism for downregulating activating receptors in NK cells or their ligands in cancer cells. The ectodomain shedding of immune receptors or ligands are therapeutic targets in cancer immunology and peculiarly relevant in NK cells, given how receptor/ligand density tips the balance to the activation or inhibition of NK cell effector functions. Two classical examples are the CD16a Fc gamma-activating receptor and the MICA/B, and B7-H6 cellular stress-induced ligands. CD16a triggers antibody-dependent cellular cytotoxicity (ADCC), but CD16a shedding by ADAM17 can prevent receptor engagement, and, therefore, CD16a shedding is a target to promote the efficacy of Fc-enabled antibodies. CD16a shedding also appears to play a dual role, not only in negatively regulating ADCC but also in terminating the immune synapse to help NK cells disengage and move to the next target cell. Furthermore, stress-induced ligands serve as "kill me" signs on the surface of cancer cells, but the shedding of such ligands enables escape from NK cell recognition. Although the shedding of stress-induced ligands is a mechanism of immune evasion in tumors, novel monoclonal antibodies that inhibit such shedding in a highly specific manner have an outstanding efficacy in preclinical tumor models, and one clone has transitioned to clinical trial phase for potently promoting anti-tumor immunity. We, therefore, review here some of the most impactful discoveries in the ectodomain shedding field with a special focus on NK cells and cancer to help inform the scientific community and help guide the development of novel immunotherapies.