ADAM17 as A Regulatory Checkpoint for CD16A in NK Cells

Creative Biolabs talks about the role of A Disintegrin and Metalloprotease 17 (ADAM17) as a regulatory checkpoint in CD16A cleavage. ADAM17 inhibitors may perhaps increase the potency of NK cells to produce ADCC and anti-tumor cytokines in an immunosuppressed tumor microenvironment.

ADCC of CD16A Mediated by NK Cells

NK cells are a population of lymphocytes in the innate immune system that mediate direct or indirect cytolytic activity against tumor cells and virus-infected cells without prior sensitization and release of various immunomodulatory cytokines. CD16A, the only activated FcγR on NK cells, is expressed at high levels in mature NK cells in the peripheral blood. The binding of CD16A to unconditioned target cells can induce NK cell degranulation and the production of various cytokines and chemokines.

Fig. 1 NK Cell-dependent ADCC.¹

Regulation of CD16A Surface Density by ADAM17

Unlike other activating receptors expressed by NK cells, the surface expression of CD16A undergoes rapid down-regulation within a few minutes, induced by the involvement of antibody-coated target cells as well as by other activating receptors and various cytokines.

ADAM17 is constitutively expressed on the surface of NK cells and cleaves substrates in a cis manner at extracellular sites close to the cell membrane. Recombinant ADAM17 cleaves the CD16A peptide at the same location. Several studies have demonstrated that truncation of the length of the proximal cleavage region of the CD16A membrane, or replacement of amino acids near the ADAM17 cleavage site, can prevent CD16A cleavage by ADAM17.

Role of CD16A Cleavage in NK Cell Regulation

CD16A is associated with Fcγ and the CD3ξ chain and may be the most potent activating receptor for NK cells.

• CD16A alone triggers degranulation of resting NK cells, whereas NKG2D and natural cytotoxic receptors need to work together to induce NK cell activation.
• Inhibitory receptors transmit negative feedback signals that inhibit or counteract most activating receptors in NK cells, whereas CD16A overcomes inhibitory signals.

Several studies have shown that preventing CD16A from being cleaved increases the strength and duration of receptor signaling, as well as the time it takes for NK cells to produce IFN-γ.

ADAM17 Acts as A Regulatory Checkpoint

• Immune checkpoints can prevent the immune system from responding to excessive tissue damage. ADAM17 can act as a regulatory checkpoint for CD16A, promoting the separation of NK cells from antibody-encapsulated target cells and reducing signaling through this activated receptor.
• Blocking the activity of ADAM17 may enhance the effector function of NK cells in the tumor microenvironment and improve the therapeutic efficacy of tumor-targeted monoclonal antibodies that expand NK cells against overt metastasis and induced ADCC.

ADAM17 inhibitors are being developed and good progress is being made in generating ADAM17 function-blocking antibodies.

At Creative Biolabs, we are dedicated to the development of checkpoint inhibitors for cancer immunotherapy with the aim of promoting robust and durable immune responses in immunosuppressed tumor microenvironments.

Reference

1. Wu, Jianming, et al. "Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy." Journal of leukocyte biology 105.6 (2019): 1297-1303.

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