Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Abstract

Human NK cell antitumor activities involve Ab-dependent cell-mediated cytotoxicity (ADCC), which is a key mechanism of action for several clinically successful tumor-targeting therapeutic mAbs. Human NK cells exclusively recognize these Abs by the Fcγ receptor CD16A (FcγRIIIA), one of their most potent activating receptors. Unlike other activating receptors on NK cells, CD16A undergoes a rapid down-regulation in expression by a proteolytic process following NK cell activation with various stimuli. In this review, the role of a disintegrin and metalloproteinase-17 (ADAM17) in CD16A cleavage and as a regulatory checkpoint is discussed. Several studies have examined the effects of inhibiting ADAM17 or CD16A cleavage directly during NK cell engagement of Ab-coated tumor cells, which resulted in strengthened Ab tethering, decreased tumor cell detachment, and enhanced CD16A signaling and cytokine production. However, the effects of either manipulation on ADCC have varied between studies, which may be due to dissimilar assays and the contribution of different killing processes by NK cells. Of importance is that NK cells under various circumstances, including in the tumor microenvironment of patients, down-regulate CD16A and this appears to impair their function. Considerable progress has been made in the development of ADAM17 inhibitors, including human mAbs that have advantages of high specificity and increased half-life in vivo. These inhibitors may provide a therapeutic means of increasing ADCC potency and/or antitumor cytokine production by NK cells in an immunosuppressive tumor microenvironment, and if used in combination with tumor-targeting Abs or NK cell-based adoptive immunotherapies may improve their efficacy.

Keywords: ADAM17; antibody; immunotherapy.

Figure 1.. Antibody-dependent cell-mediated cytotoxicity (ADCC) by human NK cells.

Tumor-targeting therapeutic mAbs are solely recognized by the Fcγ receptor CD16A (FcγRIIIA) on human NK cells, which induces their activation and release of cytotoxic components and various immune-modulating cytokines.

Figure 2.. CD16A is cleaved by ADAM17.

CD16A cleavage occurs at a specific extracellular location proximal to the cell membrane, as indicated. Exchange of serine-197 for a proline residue prevents CD16A cleavage by ADAM17.

Figure 3.. Illustration of CD16A cleavage in the tumor microenvironment and impairment of ADCC by NK cells.

Blocking ADAM17 in NK cells may reduce CD16A downregulation on tumor infiltrating NK cells and increase their ADCC potency.