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

Esther M de Kruijf1, Anita Sajet1, Johanna GH van Nes1, Hein Putter2, Vincent THBM Smit3, Robert A Eagle4, Insiya Jafferji4, John Trowsdale4, Gerrit Jan Liefers1, Cornelis JH van de Velde1 and Peter JK Kuppen1*

Author Affiliations

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

2 Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands

3 Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

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

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BMC Cancer 2012, 12:24  doi:10.1186/1471-2407-12-24

Published: 18 January 2012



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.


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.


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.


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.

ULBP; MIC; NKG2D ligand; breast cancer; immune evasion