Obstructing Shedding of Mic: the Way Forward for Cancer Treatment

One of the immunosurveillance mechanisms of the immune system is the expression of Major Histocompatibility Complex class I-related chain molecules A and B (MIC-A and B) on tumor cell surface. MIC-A and B are the ligands of an activating receptor, NKG2D expressed on the natural Killer cells (NK), therefore binding of NK cells to tumor cells through the interaction between NKG2D and MIC-A or MIC-B induces cytolysis of tumor cells. However, clinical observations of most of the human epithelial tumors are found to be MIC-positive rather than MICnegative, suggesting a functional compromise of the MIC ligand-NKG2D receptor system in cancer patients and therefore allow the growth of MIC positive tumor cells. This is made possible by the release of soluble forms of MIC-A/B from tumor cells which down regulates the NKG2D surface expression on effector cells. This review article therefore sought to discuss the mechanisms underlining the shedding of MIC from tumor cells and how they can be explored by researchers to design drugs for anti-cancer treatment. A literature search on the possible causes of MIC shedding was done. Endoplasmic reticulum protein 5 (ERp5) and A Disintegrin And Metalloproteinase (ADAM10 and ADAM17) have been implicated as responsible for the MIC shedding. Also the α3 ectodomain of the MIC has been identified as target site for these shedding agents. Anti-cancer drugs can possibly be designed using known inhibitors of ERp5, ADAM10 and ADAM17. We also believe, producing therapeutically effective amount of a purified antibody or a polypeptide comprising an antigen-binding fragment thereof that specifically binds to the α3 ectodomain of a MIC polypeptide is the way forward for cancer treatment.