NKG2D and MICA/B shedding: a 'tag game' between NK cells and malignant cells

Abstract

Natural killer (NK) cells are innate lymphocytes with cytotoxic functions and recognise target cells with the NK group 2D (NKG2D) receptor. Tumor cells are marked for NK-cell-mediated destruction upon expression of MICA and MICB (MICA/B), which are NKG2D ligands upregulated by many human cancers in response to cellular stress pathways associated with malignant transformation such as DNA damage and accumulation of misfolded proteins. However, MICA/B proteins are downregulated by tumor cells via intriguing molecular mechanisms, such as post-translational modifications in which the external domains of MICA/B are proteolytically cleaved by surface proteases and shed into the extracellular space. MICA/B shedding by cancer cells causes effective escape from NKG2D recognition and allows the development of cancers. Patients frequently have increased concentrations of soluble MICA/B molecules shed in the blood plasmas and sera, thus indicating that MICA/B shedding is a therapeutic target in immune-oncology. Here, we review the clinical significance of MICA/B shedding in cancer as well as novel immunotherapeutic approaches that aim to restore NKG2D-mediated surveillance. We also briefly discuss potential roles of MICA/B shedding beyond oncology, such as in viral infections and immune tolerance. This review will help to inform the future developments of NKG2D-based immunotherapies.

Keywords: MICA and MICB; NK cells; NKG2D; cancer immunotherapy; proteolytic shedding.

Figure 1

MICA/B shedding is an immunotherapeutic target in cancer. (a) Surface MICA/B proteins are cleaved in a multistep process that involves the MICA/B alpha‐3 domain, ERp5 and proteases. The soluble MICA/B proteins can bind to NKG2D on NK cells and chronically inhibit them via mechanisms that are not well known yet. (b) MICA/B shedding can be inhibited by monoclonal antibodies that shield the alpha‐3 domain and block, via steric hindrance, the interactions with ERp5 and the proteases. Consequently, these antibodies restore NKG2D recognition and trigger NK‐cell‐mediated killing of tumor cells. The antibodies also bind to Fc activating receptors, such as CD16a, on NK cells and trigger antibody‐dependent cellular cytotoxicity. (c) A subset of patients have tumor cells that lack MICA/B expression, but this limitation can be bypassed with epigenetic drugs that trigger MICA/B mRNA expressions such as HDAC inhibitors (HDACi) and hypomethylating agents. The same can occur upon treatments with DNA‐alkylating agents and proteasome inhibitors. These drugs can be combined with alpha‐3 domain antibodies that inhibit the MICA/B shedding, thus causing high levels of surface MICA/B for subsequent immune reaction. (d) Chimeric NKG2D receptor T cells, here abbreviated as chimeric NKG2D T cells, are highly responsive to NKG2D ligand⁺ tumor cells, but the MICA/B shedding interferes with the efficacy of this immunotherapeutic approach. As such, inhibition of MICA/B shedding with alpha‐3 domain antibodies may enable the tumor cell targeting by chimeric NKG2D T cells and promote the immunoreaction against cancers.