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

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.