NKG2D ligand tumor expression and association with clinical outcome in early breast cancer patients: an observational study

BMC Cancer

Peter JK Kuppen¹  Cornelis JH van de Velde¹  Gerrit Jan Liefers¹  John Trowsdale²  Insiya Jafferji²  Robert A Eagle²  Vincent THBM Smit⁴  Hein Putter³  Johanna GH van Nes¹  Anita Sajet¹  Esther M de Kruijf¹ 

[1]Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands

[2]Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrookes Hospital, Hills Road, Cambridge, UK

[3]Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands

[4]Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

关键词: immune evasion;    breast cancer;    NKG2D ligand;    MIC;    ULBP;   

Others  :  1080583
DOI  :  10.1186/1471-2407-12-24

 received in 2011-09-01, accepted in 2012-01-18,  发布年份 2012

【 摘 要 】

Background

Cell surface NKG2D ligands (NKG2DL) bind to the activating NKG2D receptor present on NK cells and subsets of T cells, thus playing a role in initiating an immune response. We examined tumor expression and prognostic effect of NKG2DL in breast cancer patients.

Methods

Our study population (n = 677) consisted of all breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Formalin-fixed paraffin-embedded tumor tissue was immunohistochemically stained with antibodies directed against MIC-A/MIC-B (MIC-AB), ULBP-1, ULBP-2, ULBP-3, ULBP-4, and ULBP-5.

Results

NKG2DL were frequently expressed by tumors (MIC-AB, 50% of the cases; ULBP-1, 90%; ULBP-2, 99%; ULBP-3, 100%; ULBP-4, 26%; ULBP-5, 90%) and often showed co-expression: MIC-AB and ULBP-4 (p = 0.043), ULBP-1 and ULBP-5 (p = 0.006), ULBP-4 and ULBP-5 (p < 0.001). MIC-AB (p = 0.001) and ULBP-2 (p = 0.006) expression resulted in a statistically significant longer relapse free period (RFP). Combined expression of these ligands showed to be an independent prognostic parameter for RFP (p < 0.001, HR 0.41). Combined expression of all ligands showed no associations with clinical outcome.

Conclusions

We demonstrated for the first time that NKG2DL are frequently expressed and often co-expressed in breast cancer. Expression of MIC-AB and ULBP-2 resulted in a statistically significant beneficial outcome concerning RFP with high discriminative power. Combination of all NKG2DL showed no additive or interactive effect of ligands on each other, suggesting that similar and co-operative functioning of all NKG2DL can not be assumed. Our observations suggest that among driving forces in breast cancer outcome are immune activation on one site and tumor immune escape on the other site.

【 授权许可】

   
2012 de Kruijf et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005, 55:74-108.
• [2]Early breast cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 365:1687-1717.
• [3]Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ: Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007, 18:1133-1144.
• [4]Dunn GP, Old LJ, Schreiber RD: The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004, 21:137-148.
• [5]Dunn GP, Old LJ, Schreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol 2004, 22:329-360.
• [6]Cabrera T, Angustias FM, Sierra A, Garrido A, Herruzo A, Escobedo A, Fabra A, Garrido F: High frequency of altered HLA class I phenotypes in invasive breast carcinomas. Hum Immunol 1996, 50:127-134.
• [7]de Kruijf EM, van Nes JG, Sajet A, Tummers QR, Putter H, Osanto S, Speetjens FM, Smit VT, Liefers GJ, van d V, Kuppen PJ: The Predictive Value of HLA Class I Tumor Cell Expression and Presence of Intratumoral Tregs for Chemotherapy in Patients with Early Breast Cancer. Clin Cancer Res 2010, 16:1272-1280.
• [8]Madjd Z, Spendlove I, Moss R, Bevin S, Pinder SE, Watson NF, Ellis I, Durrant LG: Upregulation of MICA on high-grade invasive operable breast carcinoma. Cancer Immun 2007, 7:17.
• [9]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, 15:6993-7002.
• [10]McGivary 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, 127:1412-20.
• [11]Champsaur M, Lanier LL: Effect of NKG2D ligand expression on host immune responses. Immunol Rev 2010, 235:267-285.
• [12]Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T: Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999, 285:727-729.
• [13]Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ: 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.
• [14]Stern-Ginossar N, Mandelboim O: An integrated view of the regulation of NKG2D ligands. Immunology 2009, 128:1-6.
• [15]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, 58:641-652.
• [16]Watson NF, Spendlove I, Madjd Z, McGilvray R, Green AR, Ellis IO, Scholefield JH, Durrant LG: Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer 2006, 118:1445-1452.
• [17]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, 62:6178-6186.
• [18]Raffaghello L, Prigione I, Airoldi I, Camoriano M, Levreri I, Gambini C, Pende D, Steinle A, Ferrone S, Pistoia V: Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia 2004, 6:558-568.
• [19]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 USA 2001, 98:11521-11526.
• [20]Diefenbach A, Jensen ER, Jamieson AM, Raulet DH: Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001, 413:165-171.
• [21]Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH: NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008, 28:571-580.
• [22]Wiemann K, Mittrucker HW, Feger U, Welte SA, Yokoyama WM, Spies T, Rammensee HG, Steinle A: Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo. J Immunol 2005, 175:720-729.
• [23]van Nes JohannaGH, de Kruijf EstherM, Faratian Dana, van de Velde CornelisJH, Putter Hein, Falconer Claire, Smit VincentTHBM, Kay Charlene, van de Vijver MarcJ, Kuppen PeterJK, Bartlett JohnMS: Analysis of untreated early breast cancer challenges the prognostic role of COX2 expression. Breast Cancer Res Treat 2009, 125:671-85.
• [24]Eagle RA, Flack G, Warford A, Martinez-Borra J, Jafferji I, Traherne JA, Ohashi M, Boyle LH, Barrow AD, Caillat-Zucman S, Young NT, Trowsdale J: Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G. PLoS One 2009, 4:e4503.
• [25]Eagle RA, Traherne JA, Hair JR, Jafferji I, Trowsdale J: ULBP6/RAET1L is an additional human NKG2D ligand. Eur J Immunol 2009, 39:3207-3216.
• [26]Putter H, Fiocco M, Geskus RB: Tutorial in biostatistics: competing risks and multi-state models. Stat Med 2007, 26:2389-2430.
• [27]Groh V, Wu J, Yee C, Spies T: Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002, 419:734-738.