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.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…It is interesting to suggest that additional ligands [e.g., PVR and NKp30 ligands (232)] that are shed by cancer cells may also be targeted in a similar fashion to increase ADCC. Moreover, studies focused on CD16-mediated-killing demonstrate that CD16 undergoes significant proteolytic downregulation following activation (251). CD16 shedding is regulated through metalloproteases such as ADAM17 (252,253).…”

“…This mechanism may serve to facilitate NK cell detachment from targets and thereby increase their mobility (254). Inhibition of CD16 shedding through ADAM17 blockade may increase NK cell activation in the TME, thereby potentiating antibody treatments targeting NK cells (251,255,256). Sustaining this CD16 mediated activity may be especially important, as the Cerwenka group showed that NK cell engagement through CD16 might prime NK cells against cancers by providing them with memory-like effects (257).…”

Mechanisms of Resistance to NK Cell Immunotherapy

“…Further, NK cells from patients treated with rituximab showed a CD16 downregulation that could last up to 48 hours post infusion [214]. In line with this observation, CD16 stimulation may induce either receptor internalization or shedding on NK cells via ADAM17 [214,215]. Along these lines, strategies targeting tumor ADAMs may synergize with ADCC, although it is still debated whether ADAM17-mediated CD16 cleavage could induce NK cell detachment from the target cell and eventually favor tumor escape.…”

Combination of pembrolizumab and 125I attenuates the aggressiveness of non‑small cell lung cancer

“…In particular, ADAM17 is a potential source of deregulation in the tumor microenvironment and adds an additional level of complexity to the manipulation of these natural systems, which also results in the resistance to chemo-/radiotherapy via the targeted signaling activation (45,46). ADAM17 can be considered as the therapeutic targeting when over activated in the tumor cells either alone or in combination with other treatment, including chemotherapy and radiotherapy (47,48). On the other hand, ADAM17 was discovered as a crucial mediator of resistance to radiotherapy, which can be considered as a therapeutic target when it overexpresses in tumor cells either alone or in combination with other immune modulating treatment.…”