Abstract
The activating receptor NKG2D (natural killer group 2, member D) of natural killer (NK) cells promotes tumor immune surveillance by targeting ligands selectively induced on cancer cells, and thus having an important role in antitumor immune response. Because these ligands are not widely expressed on healthy adult tissue, NKG2D ligands may present as useful target for immunotherapeutic approaches in cancer. In this study, to elucidate the role of NKG2D–NKG2D ligand interaction in thymoma tissues and to evaluate the potential role of NKG2D ligands as therapeutic target for thymoma, we examined the expression of NKG2D and its specific ligands: MICA (major histocompatibility complex class I chain-related protein A), MICB (major histocompatibility complex class I chain-related protein B) and ULBP (UL16-binding protein) in 36 thymomas (6 subtype A, 6 subtype AB, 8 subtype B1, 5 subtype B2, 6 subtype B3 and 5 subtype C), 15 thymic atrophy and 8 thymic hyperplasia by immunohistochemistry and reverse transcription-real-time-PCR methods. We demonstrated that both mRNA and protein levels of NKG2D, MICA, MICB and ULBP were upregulated in six types of thymomas compared with those in atrophic thymus or proliferating thymus. Furthermore, the NKG2D ligands were found to be frequently coexpressed on thymoma cells. Furthermore, the expression of MICA, MICB and ULBP in subtype C was higher compared with those in subtype A, AB, B1, B2 and B3. Thus, we concluded that high expressions of NKG2D, MICA, MICB and ULBP1 were shown in patients with thymoma, and this may enhance the recognition function of NK cells to eliminate tumor cells. MICA, MICB and ULBP presented an attractive target for thymoma therapy. The abnormal expression of NKG2D, MICA, MICB and ULBP1 can provide us with evidence of the occurrence of thymoma and could also be used as a target in the treatment of thymoma.
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References
Tomaszek S, Wigle DA, Keshavjee S, Fischer S . Thymomas: review of current clinical practice. Ann Thorac Surg 2009; 87: 1973–1980.
Wilkins KB, Sheikh E, Green R, Patel M, George S, Takano M et al. Clinical and pathologic predictors of survival in patients with thymoma. Ann Surg 1999; 230: 562–572.
Samarakoon A, Chu H, Malarkannan S . Murine NKG2D ligands: 'Double, double toil and trouble'. Mol Immunol 2009; 46: 1011–1019.
Malhotra A, Shanker A . NK cells: immune cross-talk and therapeutic implications. Immunotherapy 2011; 3: 1143–1166.
Spear P, Wu MR, Sentman ML, Sentman CL . NKG2D ligands as therapeutic targets. Cancer Immun 2013; 13: 8.
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL et al. Activation of natural killer cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999; 285: 727–729.
Champsaur M, Lanier LL . Effect of NKG2D ligand expression on host immune responses. Immunol Rev 2010; 235: 267–285.
Fernández-Messina L, Reyburn HT, Valés-Gómez M . Human NKG2D-ligands: cell biology strategies to ensure immune recognition. Front Immunol 2012; 3: 299.
Ramutton T, Buccheri S, Dieli F, Todaro M, Stassi G, Meraviglia S . γδ T cells as a potential tool in colon cancer immunotherapy. Immunotherapy 2014; 6: 989–999.
Crane CA, Austgen K, Haberthur K, Hofmann C, Moyes KW, Avanesyan L et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci USA 2014; 111: 12823–12828.
Müller-Hermelink HK, Wilisch A, Schultz A, Marx A . Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma. Arch Histol Cytol 1997; 60: 9–28.
Miki Y, Hamada K, Yoshino T, Miyatani K, Takahashi K . Type AB thymoma is not a mixed tumor of type A and type B thymomas, but a distinct type ofthymoma. Virchows Arch 2014; 464: 725–734.
Ströbel P, Hartmann E, Rosenwald A, Kalla J, Ott G, Friedel G et al. Corticomedullary differentiation and maturational arrest in thymomas. Histopathology 2014; 64: 557–566.
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: 19–29.
Conejo-Garcia JR, Benencia F, Courreges MC, Gimotty PA, Khang E, Buckanovich RJ et al. Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28- antitumor T cells. Cancer Res 2004; 64: 2175–2182.
Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008; 28: 571–580.
Cosman D, Müllberg J, Sutherland CL, Chin W, Armitage R, Fanslow W et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 2001; 14: 123–133.
Diefenbach A, Jensen ER, Jamieson AM, Raulet DH . Rae1 and H60 ligands of the NKG2Dreceptor stimulate tumour immunity. Nature 2001; 413: 165–171.
Hagemann-Jensen M, Uhlenbrock F, Kehlet S, Andresen L, Gabel-Jensen C, Ellgaard L et al. The selenium metabolite methylselenol regulates the expression of ligands that trigger immune activation through the lymphocyte receptor NKG2D. J Biol Chem 2014; 289: 31576–31590.
Crane CA, Austgen K, Haberthur K, Hofmann C, Moyes KW, Avanesyan L et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci USA 2014; 111: 12823–12828.
Uhlenbrock F, Hagemann-Jensen M, Kehlet S, Andresen L, Pastorekova S, Skov S . The NKG2D ligand ULBP2 is specifically regulated through an invariant chain-dependent endosomal pathway. J Immunol. 2014; 193: 1654–1665.
Acknowledgements
This work was supported by grants from the Medical Science and Technique Foundation of Henan (2011020073) and National Natural Science Foundation of China (No. 81172874).
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Xuan, X., Zhang, J., Hu, G. et al. Upregulated expression of NKG2D and its ligands give potential therapeutic targets for patients with thymoma. Cancer Gene Ther 22, 368–374 (2015). https://doi.org/10.1038/cgt.2015.29
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DOI: https://doi.org/10.1038/cgt.2015.29