Stress-induced MICA and MICB molecules in oncology

Abstract

MICA and MICB molecules, MHC class I chain-related proteins, are expressed on the membranes of damaged, transformed or infected cells. These glycoproteins bind to the NKG2D receptor of NK cells, resulting in their activation and cytotoxic response against MICA- and/or MICB-expressing cells. Expression of NKG2D receptor ligands allows the elimination of tumor and damaged cells. Soluble forms of MICA/B proteins are produced as a result of protein cleavage. Binding of soluble ligands to NKG2D receptors causes their internalization and degradation, leading to a decrease in NK cell activity. Malignant growth of gastrointestinal tissues, pancreas, liver, kidney, lung, skin, and blood cancers is accompanied by increased concentration of soluble MICA/B in blood plasma of the patients. High concentrations of these proteins are associated with lower overall and recurrence-free survival in the patients. Soluble MICA/B contribute to immunosuppressive tumor microenvironment, and increase in their plasma contents is considered an index of tumor escape from the immune surveillance. The role of MICA/B protein changes during carcinogenesis is also under studies. At the early stage of tumor formation, these proteins contribute to activation of NK cells and elimination of transformed cells, whereas, at the later stage of this process, the increased production of its soluble forms leads to a decrease in anti-tumor activity of NK cells. Standard cancer treatment, such as chemotherapy, is accompanied by increased density of these molecules on the tumor cells. In addition, preclinical studies show that inhibition of MICA/B shedding with antibodies or their derivatives may also promote the anti-tumor activity of NK cells. This review summarizes basic information on the biology of MICA/B molecules, their expression by normal and transformed cells, elucidates the role of these molecules in anti-tumor immune surveillance, and provides information on the potential use of MICA/B in diagnosis and therapy of malignant diseases.