NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy

Abstract

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.

High-Throughput MICA/B Genotyping of Over Two Million Samples: Workflow and Allele Frequencies

“…Therefore, these alleles might contribute to the disease prevalence in different populations. Indeed, A5.1-carriers have been associated with an increased risk for several types of cancer and higher levels of sMICA seem to have a negative prognostic value for tumor patient survival (18,27,(42)(43)(44). To reactivate a patient's NK cells, the reduction of soluble NKG2D ligands is a promising approach.…”

“…Current strategies comprise the inhibition of enzymes responsible for shedding as well as blocking the cleavage sites with therapeutic antibodies. Most likely, the efficacy of some of these new drugs will be limited to certain MICA/B alleles which increases the need for reliable genotyping (18,45).…”

“…Moreover, our amplicon strategy does not include the 5 ′ and 3 ′ UTRs of MICA/B which contain additional polymorphic positions (49,50). Some of them influence (s)MICA/B expression which varies between different alleles (18,(51)(52)(53). However, to the best of our knowledge, there are no studies, which address the effects of donor MICA/B variations outside the exons in hematopoietic stem cell transplantation.…”

“…Since high levels of both forms of soluble MICA and MICB (sMICA/B) have been found in various cancers, the release of MIC proteins is thought to be one cause for cancer immune escape. sMICA/B are therefore considered promising targets for immunotherapy (17)(18)(19)(20).…”

Tissue-autonomous immune response regulates stress signalling during hypertrophy

“…These markers are sensed by the immune 504 system, which in turn eradicates the potentially harmful cells. (Jung et al, 2012;Vantourout et 505 al., 2014;Schmiedel and Mandelboim, 2018). However, the immune surveillance theory 506 remains controversial, since tumor-associated inflammation was also shown to promote rather 507 than suppress tumor growth (Balkwill and Mantovani, 2001;Mantovani et al, 2008).…”