MICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer

BMC Cancer

Hanbyoul Cho⁶  Joon-Yong Chung⁶  Sunghoon Kim²  Till Braunschweig⁵  Tae Heung Kang⁴  Jennie Kim⁶  Eun Joo Chung¹  Stephen M Hewitt⁶  Jae-Hoon Kim³ 

[1] Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

[2] Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

[3] Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea

[4] Department of Immunology, College of Medicine, Konkuk University, Chungju, Korea

[5] Institute of Pathology, RWTH Aachen University, Aachen, Germany

[6] Tissue Array Research Program, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1500, Bethesda, MD 20892, USA

关键词: NKG2D ligands;    Immunohistochemistry;    Tissue microarray;    Cervical cancer;   

Others  :  1117877
DOI  :  10.1186/1471-2407-14-957

 received in 2014-09-27, accepted in 2014-12-11,  发布年份 2014

【 摘 要 】

Background

NKG2D (natural killer group 2, member D) is thought to play an important role in mediating the activation of anticancer immune response. Expression of NKG2D ligands (NKG2DLs) is pronounced in malignancies and the heterogeneity of NKG2DL expression remains unclear. Here, we investigate the expression and clinical significance of NKG2DLs in cervical cancer.

Methods

Immunohistochemical analyses of MICA/B, ULBP1, ULBP2, ULBP3, RAET1E, and RAET1G were performed using tissue microarray analysis of 200 cervical cancers, 327 high-grade cervical intraepithelial neoplasias (CINs), 99 low-grade CINs, and 541 matched nonadjacent normal cervical epithelial tissues and compared the data with clinicopathologic variables, including the survival of cervical cancer patients.

Results

MICA/B, ULBP1, and RAET1E expression was higher in cervical cancer than in low-grade CIN (p < 0.001, p = 0.012, p = 0.013, respectively) and normal cervix (all p < 0.001). Among these markers, expression of ULBP1 was significantly different depending on patient tumor stage (p = 0.010) and tumor size (p = 0.045). ULBP1 expression was correlated with MICA/B (p < 0.001) and ULBP2 (p = 0.002) expression in cervical cancer. While MICA/B+ or ULBP1+ patients had improved disease-free survival time (p = 0.027 and p = 0.009, respectively) relative to that of the low expression group, RAET1E+ or RAET1G+ was correlated with shorter survival time (p = 0.018 and p = 0.029, respectively). However, in terms of overall survival, the ULBP1+ group had significantly longer survival time than the low expression group (p = 0.009). Multivariate analysis indicated that MICA/B+/ULBP1+ (HR = 0.16, p = 0.015) and ULBP1+ (HR = 0.31, p = 0.024) are independent prognostic factors of disease-free survival in cervical cancer.

Conclusions

High expression of either ULBP1 or MICA/B and ULBP1 combined is an indicator of good prognosis in cervical cancer, suggesting their potential utility as prognostic tests in clinical assessment.

【 授权许可】

   
2014 Cho et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Sankaranarayanan R, Ferlay J: Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol 2006, 20(2):207-225.
• [2]Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S: Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003, 88(1):63-73.
• [3]Dalstein V, Riethmuller D, Pretet JL, Le Bail CK, Sautiere JL, Carbillet JP, Kantelip B, Schaal JP, Mougin C: Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. Int J Cancer 2003, 106(3):396-403.
• [4]Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ: HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol 2006, 208(2):152-164.
• [5]Lee WC, Lee SY, Koo YJ, Kim TJ, Hur SY, Hong SR, Kim SS, Kee MK, Rhee JE, Lee JS, Choi HS, Cho CH, Kim KT, Park JS: Establishment of a Korea HPV cohort study. J Gynecol Oncol 2013, 24(1):59-65.
• [6]Ahdieh L, Munoz A, Vlahov D, Trimble CL, Timpson LA, Shah K: Cervical neoplasia and repeated positivity of human papillomavirus infection in human immunodeficiency virus-seropositive and -seronegative women. Am J Epidemiol 2000, 151(12):1148-1157.
• [7]Trinchieri G: Biology of natural killer cells. Adv Immunol 1989, 47:187-376.
• [8]Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, Aridome K, Hokita S, Aikou T: Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000, 88(3):577-583.
• [9]Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, Jareno J, Zuil M, Callol L: Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 2002, 35(1):23-28.
• [10]Garzetti GG, Ciavattini A, Muzzioli M, Goteri G, Mannello B, Romanini C, Fabris N: Natural killer cell activity in patients with invasive cervical carcinoma: importance of a longitudinal evaluation in follow-up. Gynecol Obstet Invest 1995, 40(2):133-138.
• [11]Raulet DH: Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003, 3(10):781-790.
• [12]Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T: Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A 1996, 93(22):12445-12450.
• [13]Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, Kimura R, Miyagi T, Mochizuki K, Sasaki Y, Hayashi N: Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer 2003, 104(3):354-361.
• [14]Textor S, Durst M, Jansen L, Accardi R, Tommasino M, Trunk MJ, Porgador A, Watzl C, Gissmann L, Cerwenka A: Activating NK cell receptor ligands are differentially expressed during progression to cervical cancer. Int J Cancer 2008, 123(10):2343-2353.
• [15]Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A: Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 2003, 100(7):4120-4125.
• [16]Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A: Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 2002, 62(21):6178-6186.
• [17]Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000, 92(3):205-216.
• [18]Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002, 3(11):991-998.
• [19]McGilvray RW, Eagle RA, Watson NF, Al-Attar A, Ball G, Jafferji I, Trowsdale J, Durrant LG: NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting. Clin Cancer Res 2009, 15(22):6993-7002.
• [20]Dunn GP, Old LJ, Schreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol 2004, 22:329-360.
• [21]Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD: IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001, 410(6832):1107-1111.
• [22]Cerwenka A, Baron JL, Lanier LL: Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci U S A 2001, 98(20):11521-11526.
• [23]Diefenbach A, Jensen ER, Jamieson AM, Raulet DH: Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001, 413(6852):165-171.
• [24]Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y: NKG2D function protects the host from tumor initiation. J Exp Med 2005, 202(5):583-588.
• [25]Stern-Ginossar N, Gur C, Biton M, Horwitz E, Elboim M, Stanietsky N, Mandelboim M, Mandelboim O: Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol 2008, 9(9):1065-1073.
• [26]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):1186-1190.
• [27]Armeanu S, Bitzer M, Lauer UM, Venturelli S, Pathil A, Krusch M, Kaiser S, Jobst J, Smirnow I, Wagner A, Steinle A, Salih HR: Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res 2005, 65(14):6321-6329.
• [28]Boissel N, Rea D, Tieng V, Dulphy N, Brun M, Cayuela JM, Rousselot P, Tamouza R, Le Bouteiller P, Mahon FX, Steinle A, Salih HR: BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J Immunol 2006, 176(8):5108-5116.
• [29]Li K, Mandai M, Hamanishi J, Matsumura N, Suzuki A, Yagi H, Yamaguchi K, Baba T, Fujii S, Konishi I: Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: high expression of ULBP2 is an indicator of poor prognosis. Cancer Immunol Immunother 2009, 58(5):641-652.
• [30]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.
• [31]Eagle RA, Traherne JA, Ashiru O, Wills MR, Trowsdale J: Regulation of NKG2D ligand gene expression. Hum Immunol 2006, 67(3):159-169.
• [32]Eagle RA, Trowsdale J: Promiscuity and the single receptor: NKG2D. Nat Rev Immunol 2007, 7(9):737-744.
• [33]McGilvray RW, Eagle RA, Rolland P, Jafferji I, Trowsdale J, Durrant LG: ULBP2 and RAET1E NKG2D ligands are independent predictors of poor prognosis in ovarian cancer patients. Int J Cancer 2010, 127(6):1412-1420.
• [34]Cao W, Xi X, Hao Z, Li W, Kong Y, Cui L, Ma C, Ba D, He W: 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):18922-18928.