Natural killer cells possess key regulatory function in various malignant diseases, including acute myeloid leukemia. NK cell activity is driven by signals received through ligands binding activating or inhibitory receptors. Their activity towards elimination of transformed or virally infected cells can be mediated through MICA, MICB and ULBP ligands binding the activating receptor NKG2D. Given the efficiency of NK cells, potential target cells developed multiple protecting mechanisms to overcome NK cells killing on various levels of biogenesis of NKG2D ligands. Targeted cells can degrade ligand transcripts via microRNAs or modify them at protein level to prevent their presence at cell surface via shedding, with added benefit of shed ligands to desensitize NKG2D receptor and avert the threat of destruction via NK cells. NK cells and their activity are also indispensable during hematopoietic stem cell transplantation, crucial treatment option for patients with malignant disease, including acute myeloid leukemia. Function of both NKG2D and its ligands is strongly affected by polymorphisms and particular allelic variants, as different alleles can play variable roles in ligand-receptor interaction, influencing NK cell function and HSCT outcome differently. For example, role of amino acid exchange at position 129 in MICA or at position 98 in MICB, as well as the role of other polymorphisms leading to different shedding of ligands, was described. Finally, match or mismatch between patient and donor in NKG2D ligands affect HSCT outcome. Having the information beyond standard HLA typing prior HSCT could be instrumental to find the best donor for the patient and to optimize effects of treatment by more precise patient-donor match. Here, we review recent research on the NKG2D/NKG2D ligand biology, their regulation, description of their polymorphisms across the populations of patients with AML and the influence of particular polymorphisms on HSCT outcome.

Cancer Biology and Therapy Laboratory School of Applied Sciences London South Bank University London United Kingdom

Department of Haematology and Oncology University Hospital Pilsen Pilsen Czechia

Department of Histology and Embryology Faculty of Medicine in Pilsen Charles University Pilsen Czechia

Hugh and Josseline Langmuir Center for Myeloma Research Center for Hematology Department of Immunology and Inflammation Imperial College London London United Kingdom

Laboratory of Tumor Biology and Immunotherapy Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czechia

NTIS Faculty of Applied Sciences University of West Bohemia Pilsen Czechia

Zobrazit více v PubMed

National Cancer Institute . Surveillance, epidemiology, and end results (SEER) program Cancer stat facts: Leukemia - acute myeloid leukemia (AML). (2016). Available at: https://seer.cancer.gov/statfacts/html/amyl.html, cited 2020 18th October.

Baragaño Raneros A, López-Larrea C, Suárez-Álvarez B. Acute myeloid leukemia and NK cells: two warriors confront each other. Oncoimmunology (2019) 8(2):e1539617.  10.1080/2162402X.2018.1539617 PubMed DOI PMC

Zhang J, Gu Y, Chen B. Mechanisms of drug resistance in acute myeloid leukemia. Onco Targets Ther (2019) 12:1937–45.  10.2147/OTT.S191621 PubMed DOI PMC

Gill S, Olson JA, Negrin RS. Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses. Biol Blood Marrow Transplant (2009) 15(7):765–76.  10.1016/j.bbmt.2009.01.019 PubMed DOI PMC

Bendall LJ, Kortlepel K, Bradstock KF, Gottlieb DJ. Natural killer cells adhere to bone marrow fibroblasts and inhibit adhesion of acute myeloid leukemia cells. Leukemia (1995) 9(6):999–1005. PubMed

Sandoval-Borrego D, Moreno-Lafont MC, Vazquez-Sanchez EA, Gutierrez-Hoya A, López-Santiago R, Montiel-Cervantes LA, et al. . Overexpression of CD158 and NKG2A Inhibitory Receptors and Underexpression of NKG2D and NKp46 Activating Receptors on NK Cells in Acute Myeloid Leukemia. Arch Med Res (2016) 47(1):55–64.  10.1016/j.arcmed.2016.02.001 PubMed DOI

Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, et al. . Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood (2007) 109(1):323–30.  10.1182/blood-2005-08-027979 PubMed DOI

Sanchez-Correa B, Gayoso I, Bergua JM, Casado JG, Morgado S, Solana R, et al. . Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol (2012) 90(1):109–15.  10.1038/icb.2011.15 PubMed DOI

Valhondo I, Hassouneh F, Lopez-Sejas N, Pera A, Sanchez-Correa B, Guerrero B, et al. . Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia. Cancers (Basel) (2020) 12(8):2171.  10.3390/cancers12082171 PubMed DOI PMC

Godal R, Bachanova V, Gleason M, McCullar V, Yun GH, Cooley S, et al. . Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG2A and LIR-1 blockade. Biol Blood Marrow Transplant (2010) 16(5):612–21.  10.1016/j.bbmt.2010.01.019 PubMed DOI PMC

Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood (2010) 115(21):4293–301.  10.1182/blood-2009-05-222190 PubMed DOI PMC

Hercend T, Takvorian T, Nowill A, Tantravahi R, Moingeon P, Anderson KC, et al. . Characterization of natural killer cells with antileukemia activity following allogeneic bone marrow transplantation. Blood (1986) 67(3):722–8. 10.1182/blood.V67.3.722.722 PubMed DOI

Arvindam US, Aguilar EG, Felices M, Murphy W, Miller J. Chapter 16 - Natural Killer Cells in GvHD and GvL. In: Socié G, Zeiser R, Blazar BR, editors. Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation (Second Edition). Academic Press, Elsevier; (2019). p. 275–92.

Zingoni A, Ardolino M, Santoni A, Cerboni C. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Front Immunol (2013) 3:408.  10.3389/fimmu.2012.00408 PubMed DOI PMC

Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, et al. . Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med (1999) 190(10):1505–16.  10.1084/jem.190.10.1505 PubMed DOI PMC

Sivori S, Vitale M, Morelli L, Sanseverino L, Augugliaro R, Bottino C, et al. . p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med (1997) 186(7):1129–36.  10.1084/jem.186.7.1129 PubMed DOI PMC

Vitale M, Bottino C, Sivori S, Sanseverino L, Castriconi R, Marcenaro E, et al. . NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J Exp Med (1998) 187(12):2065–72.  10.1084/jem.187.12.2065 PubMed DOI PMC

Espinoza JL, Takami A, Onizuka M, Sao H, Akiyama H, Miyamura K, et al. . NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies. Haematologica (2009) 94(10):1427–34.  10.3324/haematol.2009.008318 PubMed DOI PMC

Wolan DW, Teyton L, Rudolph MG, Villmow B, Bauer S, Busch DH, et al. . Crystal structure of the murine NK cell-activating receptor NKG2D at 1.95 A. Nat Immunol (2001) 2(3):248–54.  10.1038/85311 PubMed DOI

Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity (2002) 17(1):19–29.  10.1016/s1074-7613(02)00333-3 PubMed DOI

Glienke J, Sobanov Y, Brostjan C, Steffens C, Nguyen C, Lehrach H, et al. . The genomic organization of NKG2C, E, F, and D receptor genes in the human natural killer gene complex. Immunogenetics (1998) 48(3):163–73.  10.1007/s002510050420 PubMed DOI

Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL, et al. . An activating immunoreceptor complex formed by NKG2D and DAP10. Science (1999) 285(5428):730–2.  10.1126/science.285.5428.730 PubMed DOI

Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. . Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science (1999) 285(5428):727–9.  10.1126/science.285.5428.727 PubMed DOI

Hayashi T, Imai K, Morishita Y, Hayashi I, Kusunoki Y, Nakachi K. Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance. Cancer Res (2006) 66(1):563–70.  10.1158/0008-5472.CAN-05-2776 PubMed DOI

Hara R, Onizuka M, Matsusita E, Kikkawa E, Nakamura Y, Matsushita H, et al. . NKG2D gene polymorphisms are associated with disease control of chronic myeloid leukemia by dasatinib. Int J Hematol (2017) 106(5):666–74.  10.1007/s12185-017-2294-1 PubMed DOI

Stephens HA. MICA and MICB genes: can the enigma of their polymorphism be resolved? Trends Immunol (2001) 22(7):378–85.  10.1016/s1471-4906(01)01960-3 PubMed DOI

Zingoni A, Molfetta R, Fionda C, Soriani A, Paolini R, Cippitelli M, et al. . NKG2D and Its Ligands: “One for All, All for One”. Front Immunol (2018) 9:476.  10.3389/fimmu.2018.00476 PubMed DOI PMC

Kim JY, Son YO, Park SW, Bae JH, Chung JS, Kim HH, et al. . Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation. Exp Mol Med (2006) 38(5):474–84.  10.1038/emm.2006.56 PubMed DOI

Venkataraman GM, Suciu D, Groh V, Boss JM, Spies T. Promoter region architecture and transcriptional regulation of the genes for the MHC class I-related chain A and B ligands of NKG2D. J Immunol (2007) 178(2):961–9.  10.4049/jimmunol.178.2.961 PubMed DOI

Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature (2005) 436(7054):1186–90.  10.1038/nature03884 PubMed DOI PMC

Zou Z, Nomura M, Takihara Y, Yasunaga T, Shimada K. Isolation and characterization of retinoic acid-inducible cDNA clones in F9 cells: a novel cDNA family encodes cell surface proteins sharing partial homology with MHC class I molecules. J Biochem (1996) 119(2):319–28.  10.1093/oxfordjournals.jbchem.a021242 PubMed DOI

Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, et al. . Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood (2005) 105(9):3615–22.  10.1182/blood-2004-07-2585 PubMed DOI

Ghadially H, Brown L, Lloyd C, Lewis L, Lewis A, Dillon J, et al. . MHC class I chain-related protein A and B (MICA and MICB) are predominantly expressed intracellularly in tumour and normal tissue. Br J Cancer (2017) 116(9):1208–17.  10.1038/bjc.2017.79 PubMed DOI PMC

Jung H, Hsiung B, Pestal K, Procyk E, Raulet DH. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J Exp Med (2012) 209(13):2409–22.  10.1084/jem.20120565 PubMed DOI PMC

Eagle RA, Jafferji I, Barrow AD. Beyond Stressed Self: Evidence for NKG2D Ligand Expression on Healthy Cells. Curr Immunol Rev (2009) 5(1):22–34.  10.2174/157339509787314369 PubMed DOI PMC

Molinero LL, Fuertes MB, Rabinovich GA, Fainboim L, Zwirner NW. Activation-induced expression of MICA on T lymphocytes involves engagement of CD3 and CD28. J Leukoc Biol (2002) 71(5):791–7. 10.1189/jlb.71.5.791 PubMed DOI

Tamaki S, Sanefuzi N, Ohgi K, Imai Y, Kawakami M, Yamamoto K, et al. . An association between the MICA-A5.1 allele and an increased susceptibility to oral squamous cell carcinoma in Japanese patients. J Oral Pathol Med (2007) 36(6):351–6.  10.1111/j.1600-0714.2007.00539.x PubMed DOI

Ding W, Ma Y, Zhu W, Pu W, Zhang J, Qian F, et al. . Allele Facilitates the Metastasis of KRAS-Mutant Colorectal Cancer. Front Genet (2020) 11:511.  10.3389/fgene.2020.00511 PubMed DOI PMC

Fechtenbaum M, Desoutter J, Delvallez G, Brochot E, Guillaume N, Goëb V. MICA and NKG2D variants as risk factors in spondyloarthritis: a case-control study. Genes Immun (2019) 20(7):599–605.  10.1038/s41435-018-0044-x PubMed DOI PMC

Ji M, Wang J, Yuan L, Zhang Y, Zhang J, Dong W, et al. . MICA polymorphisms and cancer risk: a meta-analysis. Int J Clin Exp Med (2015) 8(1):818–26. PubMed PMC

Bahram S. MIC genes: from genetics to biology. Adv Immunol (2000) 76:1–60.  10.1016/s0065-2776(01)76018-x PubMed DOI

Pérez-Rodríguez M, Argüello JR, Fischer G, Corell A, Cox ST, Robinson J, et al. . Further polymorphism of the MICA gene. Eur J Immunogenet (2002) 29(1):35–46.  10.1046/j.0960-7420.2001.00275.x PubMed DOI

Pérez-Rodríguez M, Corell A, Argüello JR, Cox ST, McWhinnie A, Marsh SG, et al. . A new MICA allele with ten alanine residues in the exon 5 microsatellite. Tissue Antigens (2000) 55(2):162–5.  10.1034/j.1399-0039.2000.550209.x PubMed DOI

Suemizu H, Radosavljevic M, Kimura M, Sadahiro S, Yoshimura S, Bahram S, et al. . A basolateral sorting motif in the MICA cytoplasmic tail. Proc Natl Acad Sci USA (2002) 99(5):2971–6.  10.1073/pnas.052701099 PubMed DOI PMC

Ashiru O, López-Cobo S, Fernández-Messina L, Pontes-Quero S, Pandolfi R, Reyburn HT, et al. . A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008. Biochem J (2013) 454(2):295–302.  10.1042/BJ20130194 PubMed DOI

Seidel E, Le VTK, Bar-On Y, Tsukerman P, Enk J, Yamin R, et al. . Dynamic Co-evolution of Host and Pathogen: HCMV Downregulates the Prevalent Allele MICA∗008 to Escape Elimination by NK Cells. Cell Rep (2015) 10(6):968–82.  10.1016/j.celrep.2015.01.029 PubMed DOI PMC

Ashiru O, Bennett NJ, Boyle LH, Thomas M, Trowsdale J, Wills MR. NKG2D ligand MICA is retained in the cis-Golgi apparatus by human cytomegalovirus protein UL142. J Virol (2009) 83(23):12345–54.  10.1128/JVI.01175-09 PubMed DOI PMC

Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res (2015) 43(Database issue):D423–31.  10.1093/nar/gku1161 PubMed DOI PMC

Klussmeier A, Massalski C, Putke K, Schäfer G, Sauter J, Schefzyk D, et al. . High-Throughput MICA/B Genotyping of Over Two Million Samples: Workflow and Allele Frequencies. Front Immunol (2020) 11:314.  10.3389/fimmu.2020.00314 PubMed DOI PMC

Kirijas Or Paneva M, Spiroski M. MICA Polymorphism, Association with Diseases and the Role of Anti-MICA Antibodies in Organ and Stem Cell Transplantation. Macedonian J Med Sci (2013) 6:285–95.  10.3889/MJMS.1857-5773.2013.0299 DOI

Petersdorf EW, Shuler KB, Longton GM, Spies T, Hansen JA. Population study of allelic diversity in the human MHC class I-related MIC-A gene. Immunogenetics (1999) 49(7-8):605–12.  10.1007/s002510050655 PubMed DOI

Carapito R, Bahram S. Genetics, genomics, and evolutionary biology of NKG2D ligands. Immunol Rev (2015) 267(1):88–116.  10.1111/imr.12328 PubMed DOI

Radosavljevic M, Cuillerier B, Wilson MJ, Clément O, Wicker S, Gilfillan S, et al. . A cluster of ten novel MHC class I related genes on human chromosome 6q24.2-q25.3. Genomics (2002) 79(1):114–23.  10.1006/geno.2001.6673 PubMed DOI

Bacon L, Eagle RA, Meyer M, Easom N, Young NT, Trowsdale J. Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. J Immunol (2004) 173(2):1078–84.  10.4049/jimmunol.173.2.1078 PubMed DOI

Zöller T, Wittenbrink M, Hoffmeister M, Steinle A. Cutting an NKG2D Ligand Short: Cellular Processing of the Peculiar Human NKG2D Ligand ULBP4. Front Immunol (2018) 9:620.  10.3389/fimmu.2018.00620 PubMed DOI PMC

Lefranc MP. IMGT, the international ImMunoGeneTics database. Nucleic Acids Res (2001) 29(1):207–9.  10.1093/nar/29.1.207 PubMed DOI PMC

Fernández-Messina L, Ashiru O, Agüera-González S, Reyburn HT, Valés-Gómez M. The human NKG2D ligand ULBP2 can be expressed at the cell surface with or without a GPI anchor and both forms can activate NK cells. J Cell Sci (2011) 124(Pt 3):321–7.  10.1242/jcs.076042 PubMed DOI PMC

Ohashi M, Eagle RA, Trowsdale J. Post-translational modification of the NKG2D ligand RAET1G leads to cell surface expression of a glycosylphosphatidylinositol-linked isoform. J Biol Chem (2010) 285(22):16408–15.  10.1074/jbc.M109.077636 PubMed DOI PMC

Cole DK, Laugel B, Clement M, Price DA, Wooldridge L, Sewell AK. The molecular determinants of CD8 co-receptor function. Immunology (2012) 137(2):139–48.  10.1111/j.1365-2567.2012.03625.x PubMed DOI PMC

Cox ST, Arrieta-Bolaños E, Pesoa S, Vullo C, Madrigal JA, Saudemont A. RAET1/ULBP alleles and haplotypes among Kolla South American Indians. Hum Immunol (2013) 74(6):775–82.  10.1016/j.humimm.2013.01.030 PubMed DOI

Antoun A, Jobson S, Cook M, O’Callaghan CA, Moss P, Briggs DC. Single nucleotide polymorphism analysis of the NKG2D ligand cluster on the long arm of chromosome 6: Extensive polymorphisms and evidence of diversity between human populations. Hum Immunol (2010) 71(6):610–20.  10.1016/j.humimm.2010.02.018 PubMed DOI

Romphruk AV, Romphruk A, Naruse TK, Raroengjai S, Puapairoj C, Inoko H, et al. . Polymorphisms of NKG2D ligands: diverse RAET1/ULBP genes in northeastern Thais. Immunogenetics (2009) 61(9):611–7.  10.1007/s00251-009-0394-7 PubMed DOI

Gorgoulis VG, Pefani DE, Pateras IS, Trougakos IP. Integrating the DNA damage and protein stress responses during cancer development and treatment. J Pathol (2018) 246(1):12–40.  10.1002/path.5097 PubMed DOI PMC

Lakin ND, Jackson SP. Regulation of p53 in response to DNA damage. Oncogene (1999) 18(53):7644–55.  10.1038/sj.onc.1203015 PubMed DOI

Li H, Lakshmikanth T, Garofalo C, Enge M, Spinnler C, Anichini A, et al. . Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2. Cell Cycle (2011) 10(19):3346–58.  10.4161/cc.10.19.17630 PubMed DOI

Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol (2013) 31:413–41.  10.1146/annurev-immunol-032712-095951 PubMed DOI PMC

Heinemann A, Zhao F, Pechlivanis S, Eberle J, Steinle A, Diederichs S, et al. . Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D. Cancer Res (2012) 72(2):460–71.  10.1158/0008-5472.CAN-11-1977 PubMed DOI

Stern-Ginossar N, Gur C, Biton M, Horwitz E, Elboim M, Stanietsky N, et al. . Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol (2008) 9(9):1065–73.  10.1038/ni.1642 PubMed DOI

Paczulla AM, Rothfelder K, Raffel S, Konantz M, Steinbacher J, Wang H, et al. . Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature (2019) 572(7768):254–9.  10.1038/s41586-019-1410-1 PubMed DOI PMC

Gaymes TJ, Shall S, MacPherson LJ, Twine NA, Lea NC, Farzaneh F, et al. . Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes. Haematologica (2009) 94(5):638–46.  10.3324/haematol.2008.001933 PubMed DOI PMC

Gojo I, Beumer JH, Pratz KW, McDevitt MA, Baer MR, Blackford AL, et al. . A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia. Clin Cancer Res (2017) 23(3):697–706.  10.1158/1078-0432.CCR-16-0984 PubMed DOI PMC

Chandhok NS, Wei W, Bindra R, Halene S, Shyr Y, Li J, et al. . The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. a Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome. Blood (2019) 134(Supplement_1):3909–.  10.1182/blood-2019-129168 DOI

Kohl V, Flach J, Naumann N, Brendel S, Kleiner H, Weiss C, et al. . Antileukemic Efficacy in Vitro of Talazoparib and APE1 Inhibitor III Combined with Decitabine in Myeloid Malignancies. Cancers (Basel) (2019) 11(10):1493.  10.3390/cancers11101493 PubMed DOI PMC

Nice TJ, Coscoy L, Raulet DH. Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress. J Exp Med (2009) 206(2):287–98.  10.1084/jem.20081335 PubMed DOI PMC

Mattiroli F, Sixma TK. Lysine-targeting specificity in ubiquitin and ubiquitin-like modification pathways. Nat Struct Mol Biol (2014) 21(4):308–16.  10.1038/nsmb.2792 PubMed DOI

Champsaur M, Lanier LL. Effect of NKG2D ligand expression on host immune responses. Immunol Rev (2010) 235(1):267–85.  10.1111/j.0105-2896.2010.00893.x PubMed DOI PMC

Thomas M, Wills M, Lehner PJ. Natural killer cell evasion by an E3 ubiquitin ligase from Kaposi’s sarcoma-associated herpesvirus. Biochem Soc Trans (2008) 36(Pt 3):459–63.  10.1042/BST0360459 PubMed DOI

Vyas M, Reinartz S, Hoffmann N, Reiners KS, Lieber S, Jansen JM, et al. . Soluble NKG2D ligands in the ovarian cancer microenvironment are associated with an adverse clinical outcome and decreased memory effector T cells independent of NKG2D downregulation. Oncoimmunology (2017) 6(9):e1339854.  10.1080/2162402X.2017.1339854 PubMed DOI PMC

Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR. Soluble MICA in malignant diseases. Int J Cancer (2006) 118(3):684–7.  10.1002/ijc.21382 PubMed DOI

Cao W, Xi X, Hao Z, Li W, Kong Y, Cui L, et al. . RAET1E2, a soluble isoform of the UL16-binding protein RAET1E produced by tumor cells, inhibits NKG2D-mediated NK cytotoxicity. J Biol Chem (2007) 282(26):18922–8.  10.1074/jbc.M702504200 PubMed DOI

Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A, et al. . Tumor-associated MICA is shed by ADAM proteases. Cancer Res (2008) 68(15):6368–76.  10.1158/0008-5472.CAN-07-6768 PubMed DOI

Liu G, Atteridge CL, Wang X, Lundgren AD, Wu JD. The membrane type matrix metalloproteinase MMP14 mediates constitutive shedding of MHC class I chain-related molecule A independent of A disintegrin and metalloproteinases. J Immunol (2010) 184(7):3346–50.  10.4049/jimmunol.0903789 PubMed DOI PMC

Waldhauer I, Steinle A. Proteolytic release of soluble UL16-binding protein 2 from tumor cells. Cancer Res (2006) 66(5):2520–6.  10.1158/0008-5472.CAN-05-2520 PubMed DOI

Zingoni A, Vulpis E, Loconte L, Santoni A. NKG2D Ligand Shedding in Response to Stress: Role of ADAM10. Front Immunol (2020) 11:447.  10.3389/fimmu.2020.00447 PubMed DOI PMC

Sun D, Wang X, Zhang H, Deng L, Zhang Y. MMP9 mediates MICA shedding in human osteosarcomas. Cell Biol Int (2011) 35(6):569–74.  10.1042/CBI20100431 PubMed DOI

Mincheva-Nilsson L, Baranov V. Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Semin Cancer Biol (2014) 28:24–30.  10.1016/j.semcancer.2014.02.010 PubMed DOI

Sharma P, Diergaarde B, Ferrone S, Kirkwood JM, Whiteside TL. Melanoma cell-derived exosomes in plasma of melanoma patients suppress functions of immune effector cells. Sci Rep (2020) 10(1):92.  10.1038/s41598-019-56542-4 PubMed DOI PMC

Fernández-Messina L, Ashiru O, Boutet P, Agüera-González S, Skepper JN, Reyburn HT, et al. . Differential mechanisms of shedding of the glycosylphosphatidylinositol (GPI)-anchored NKG2D ligands. J Biol Chem (2010) 285(12):8543–51.  10.1074/jbc.M109.045906 PubMed DOI PMC

Song H, Kim J, Cosman D, Choi I. Soluble ULBP suppresses natural killer cell activity via down-regulating NKG2D expression. Cell Immunol (2006) 239(1):22–30.  10.1016/j.cellimm.2006.03.002 PubMed DOI

Ashiru O, Boutet P, Fernández-Messina L, Agüera-González S, Skepper JN, Valés-Gómez M, et al. . Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. Cancer Res (2010) 70(2):481–9.  10.1158/0008-5472.CAN-09-1688 PubMed DOI PMC

Boutet P, Agüera-González S, Atkinson S, Pennington CJ, Edwards DR, Murphy G, et al. . Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein. J Immunol (2009) 182(1):49–53.  10.4049/jimmunol.182.1.49 PubMed DOI

Sépult C, Bellefroid M, Rocks N, Donati K, Gérard C, Gilles C, et al. . ADAM10 mediates malignant pleural mesothelioma invasiveness. Oncogene (2019) 38(18):3521–34.  10.1038/s41388-018-0669-2 PubMed DOI PMC

McCulloch DR, Akl P, Samaratunga H, Herington AC, Odorico DM. Expression of the disintegrin metalloprotease, ADAM-10, in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor in the prostate cancer cell model LNCaP. Clin Cancer Res (2004) 10(1 Pt 1):314–23.  10.1158/1078-0432.ccr-0846-3 PubMed DOI

Ko SY, Lin SC, Wong YK, Liu CJ, Chang KW, Liu TY. Increase of disintergin metalloprotease 10 (ADAM10) expression in oral squamous cell carcinoma. Cancer Lett (2007) 245(1-2):33–43.  10.1016/j.canlet.2005.10.019 PubMed DOI

Paschen A, Sucker A, Hill B, Moll I, Zapatka M, Nguyen XD, et al. . Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B. Clin Cancer Res (2009) 15(16):5208–15.  10.1158/1078-0432.CCR-09-0886 PubMed DOI

Jinushi M, Vanneman M, Munshi NC, Tai YT, Prabhala RH, Ritz J, et al. . MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA (2008) 105(4):1285–90.  10.1073/pnas.0711293105 PubMed DOI PMC

Hilpert J, Grosse-Hovest L, Grünebach F, Buechele C, Nuebling T, Raum T, et al. . Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. J Immunol (2012) 189(3):1360–71.  10.4049/jimmunol.1200796 PubMed DOI

Nückel H, Switala M, Sellmann L, Horn PA, Dürig J, Dührsen U, et al. . The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia. Leukemia (2010) 24(6):1152–9.  10.1038/leu.2010.74 PubMed DOI

Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, et al. . Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood (2003) 102(4):1389–96.  10.1182/blood-2003-01-0019 PubMed DOI

Luo QZ, Lin L, Gong Z, Mei B, Xu YJ, Huo Z, et al. . Positive association of major histocompatibility complex class I chain-related gene A polymorphism with leukemia susceptibility in the people of Han nationality of Southern China. Tissue Antigens (2011) 78(3):178–84.  10.1111/j.1399-0039.2011.01748.x PubMed DOI

Baek IC, Shin DH, Choi EJ, Kim HJ, Yoon JH, Cho BS, et al. . Association of MICA and MICB polymorphisms with the susceptibility of leukemia in Korean patients. Blood Cancer J (2018) 8(6):58.  10.1038/s41408-018-0092-5 PubMed DOI PMC

Antoun A, Vekaria D, Salama RA, Pratt G, Jobson S, Cook M, et al. . The genotype of RAET1L (ULBP6), a ligand for human NKG2D (KLRK1), markedly influences the clinical outcome of allogeneic stem cell transplantation. Br J Haematol (2012) 159(5):589–98.  10.1111/bjh.12072 PubMed DOI

Mastaglio S, Wong E, Perera T, Ripley J, Blombery P, Smyth MJ, et al. . Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy. Blood Adv (2018) 2(4):335–46.  10.1182/bloodadvances.2017015230 PubMed DOI PMC

Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. . Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant (2016) 51(6):786–92.  10.1038/bmt.2016.20 PubMed DOI PMC

BARNES DW, CORP MJ, LOUTIT JF, NEAL FE. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. Br Med J (1956) 2(4993):626–7.  10.1136/bmj.2.4993.626 PubMed DOI PMC

Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. . Graft-versus-leukemia reactions after bone marrow transplantation. Blood (1990) 75(3):555–62. 10.1182/blood.V75.3.555.555 PubMed DOI

Mohty B, Mohty M. Long-term complications and side effects after allogeneic hematopoietic stem cell transplantation: an update. Blood Cancer J (2011) 1(4):e16.  10.1038/bcj.2011.14 PubMed DOI PMC

Ferrara JL, Reddy P. Pathophysiology of graft-versus-host disease. Semin Hematol (2006) 43(1):3–10.  10.1053/j.seminhematol.2005.09.001 PubMed DOI

Ramachandran V, Kolli SS, Strowd LC. Review of Graft-Versus-Host Disease. Dermatol Clin (2019) 37(4):569–82.  10.1016/j.det.2019.05.014 PubMed DOI

Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP. Chronic graft-versus-host disease: clinical manifestation and therapy. Bone Marrow Transplant (2001) 28(2):121–9.  10.1038/sj.bmt.1703111 PubMed DOI

Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute Graft. Anticancer Res (2017) 37(4):1547–55.  10.21873/anticanres.11483 PubMed DOI

Pérez-Simón JA, Díez-Campelo M, Martino R, Brunet S, Urbano A, Caballero MD, et al. . Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation. Br J Haematol (2005) 130(3):394–403.  10.1111/j.1365-2141.2005.05614.x PubMed DOI

Kumar S, Mohammadpour H, Cao X. Targeting Cytokines in GVHD Therapy. J Immunol Res Ther (2017) 2(1):90–9. PubMed PMC

Yu Y, Wang D, Liu C, Kaosaard K, Semple K, Anasetti C, et al. . Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice. Blood (2011) 118(18):5011–20.  10.1182/blood-2011-03-340315 PubMed DOI PMC

Reddy P. Pathophysiology of acute graft-versus-host disease. Hematol Oncol (2003) 21(4):149–61.  10.1002/hon.716 PubMed DOI

Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. . National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant (2015) 21(3):389–401.e1.  10.1016/j.bbmt.2014.12.001 PubMed DOI PMC

Zeiser R, Blazar BR. Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets. N Engl J Med (2017) 377(26):2565–79.  10.1056/NEJMra1703472 PubMed DOI

Petersdorf EW. Which factors influence the development of GVHD in HLA-matched or mismatched transplants? Best Pract Res Clin Haematol (2017) 30(4):333–5.  10.1016/j.beha.2017.09.003 PubMed DOI PMC

Kawase T, Matsuo K, Kashiwase K, Inoko H, Saji H, Ogawa S, et al. . HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. Blood (2009) 113(12):2851–8.  10.1182/blood-2008-08-171934 PubMed DOI

Heidenreich S, Kröger N. Reduction of Relapse after Unrelated Donor Stem Cell Transplantation by KIR-Based Graft Selection. Front Immunol (2017) 8:41.  10.3389/fimmu.2017.00041 PubMed DOI PMC

Isernhagen A, Malzahn D, Viktorova E, Elsner L, Monecke S, von Bonin F, et al. . The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation. EMBO Mol Med (2015) 7(11):1480–502.  10.15252/emmm.201505246 PubMed DOI PMC

Fuerst D, Neuchel C, Niederwieser D, Bunjes D, Gramatzki M, Wagner E, et al. . Matching for the MICA-129 polymorphism is beneficial in unrelated hematopoietic stem cell transplantation. Blood (2016) 128(26):3169–76.  10.1182/blood-2016-05-716357 PubMed DOI

Parmar S, Del Lima M, Zou Y, Patah PA, Liu P, Cano P, et al. . Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease. Blood (2009) 114(14):2884–7.  10.1182/blood-2009-05-223172 PubMed DOI PMC

Carapito R, Jung N, Kwemou M, Untrau M, Michel S, Pichot A, et al. . Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD. Blood (2016) 128(15):1979–86.  10.1182/blood-2016-05-719070 PubMed DOI PMC

Signori A, Crocchiolo R, Oneto R, Sacchi N, Sormani MP, Fagioli F, et al. . Chronic GVHD is associated with inferior relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors. Bone Marrow Transplant (2012) 47(11):1474–8.  10.1038/bmt.2012.58 PubMed DOI

Remberger M, Mattsson J, Hentschke P, Aschan J, Barkholt L, Svennilson J, et al. . The graft-versus-leukaemia effect in haematopoietic stem cell transplantation using unrelated donors. Bone Marrow Transplant (2002) 30(11):761–8.  10.1038/sj.bmt.1703735 PubMed DOI

Boukouaci W, Busson M, Peffault de Latour R, Rocha V, Suberbielle C, Bengoufa D, et al. . MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease. Blood (2009) 114(25):5216–24.  10.1182/blood-2009-04-217430 PubMed DOI

Gam R, Shah P, Crossland RE, Norden J, Dickinson AM, Dressel R. Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes. Front Immunol (2017) 8:380.  10.3389/fimmu.2017.00380 PubMed DOI PMC

Martin PJ, Levine DM, Storer BE, Nelson SC, Dong X, Hansen JA. Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation. Blood Adv (2020) 4(14):3224–33.  10.1182/bloodadvances.2020001927 PubMed DOI PMC

Patel SS, Rybicki LA, Yurch M, Thomas D, Liu H, Dean R, et al. . Influence of major histocompatibility complex class I chain-related gene A polymorphisms on cytomegalovirus disease after allogeneic hematopoietic cell transplantation. Hematol Oncol Stem Cell Ther (2020) 13(1):32–9.  10.1016/j.hemonc.2019.10.001 PubMed DOI

Isernhagen A, Schilling D, Monecke S, Shah P, Elsner L, Walter L, et al. . The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA. Immunogenetics (2016) 68(2):109–23.  10.1007/s00251-015-0884-8 PubMed DOI PMC

Carapito R, Aouadi I, Pichot A, Spinnhirny P, Morlon A, Kotova I, et al. . Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus-host disease in conjunction with the CMV status. Bone Marrow Transplant (2020) 55(7):1367–78.  10.1038/s41409-020-0886-5 PubMed DOI

Zuo J, Willcox CR, Mohammed F, Davey M, Hunter S, Khan K, et al. . A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D ligand binding. Sci Signal (2017) 10(481):eaai8904.  10.1126/scisignal.aai8904 PubMed DOI

Zuo J, Mohammed F, Moss P. The Biological Influence and Clinical Relevance of Polymorphism Within the NKG2D Ligands. Front Immunol (2018) 9:1820.  10.3389/fimmu.2018.01820 PubMed DOI PMC

Yoshida K, Komai K, Shiozawa K, Mashida A, Horiuchi T, Tanaka Y, et al. . Role of the MICA polymorphism in systemic lupus erythematosus. Arthritis Rheum (2011) 63(10):3058–66.  10.1002/art.30501 PubMed DOI

Norris S, Kondeatis E, Collins R, Satsangi J, Clare M, Chapman R, et al. . Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism. Gastroenterology (2001) 120(6):1475–82.  10.1053/gast.2001.24041 PubMed DOI

López-Arbesu R, Ballina-García FJ, Alperi-López M, López-Soto A, Rodríguez-Rodero S, Martínez-Borra J, et al. . MHC class I chain-related gene B (MICB) is associated with rheumatoid arthritis susceptibility. Rheumatol (Oxford) (2007) 46(3):426–30.  10.1093/rheumatology/kel331 PubMed DOI

Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y, et al. . Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature (2010) 466(7302):113–7.  10.1038/nature09114 PubMed DOI PMC

Single-Nucleotide Polymorphisms in MICA and MICB Genes Could Play a Role in the Outcome in AML Patients after HSCT