DNA damage, oncogene activation and excessive proliferation,
chromatin modulations or oxidative stress are all important hallmarks of
cancer. Interestingly, all of these abnormalities also induce a cellular stress response. By upregulating "stress-induced
ligands," damaged or transformed cells can be recognized by immune cells and cleared. The human genome encodes eight functional "stress-induced
ligands":
MICA, MICB, and ULBP1-6. All of them are recognized by a single
receptor, NKG2D, which is expressed on natural killer (NK) cells, cytotoxic T cells and other T cell subsets. The NKG2D
ligand/NKG2D-axis is well-recognized as an important mediator of anti-
tumor activity; however, patient data about the role of NKG2D
ligands in immune surveillance and escape appears conflicting. As these
ligands are often actively transcribed,
tumor cells are urged to manipulate the expression of these
ligands on post-transcriptional or post-translational level. Although our knowledge on the regulation of NKG2D
ligand expression remains fragmentary, research of the past years revealed multiple cellular mechanisms that are adopted by
tumor cells to reduce the expression of "stress-induced
ligands" and therefore escape immune recognition. Here, we review the post-transcriptional and post-translational mechanisms by which NKG2D
ligands are modulated in
cancer cells and their impact on patient prognosis.We discuss controversies and approaches to apply our understanding of the NKG2D
ligand/NKG2D-axis for
cancer therapy.