NKG2D ligand tumor expression and association with clinical outcome in early breast cancer patients: an observational study - PubMed (original) (raw)

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

Esther M de Kruijf et al. BMC Cancer. 2012.

Abstract

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.

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Figures

Figure 1

Figure 1

Representative examples of immunohistochemical stainings of primary breast cancer tissues for respectively no expression and high expression of MIC-AB (A: intensity 0 (negative); B: intensity 2 (intermediate)), ULBP-1 (C: intensity 0 (negative); D: intensity 2 (intermediate)), ULBP-2 (E: intensity 0 (negative); F: intensity 3 (strong)), ULBP-3 (G: intensity 0 (negative); H: intensity 3 (strong)), ULBP-4 (I: intensity 0 (negative); J: intensity 1 (weak)), and ULBP-5 (K: intensity 0 (negative); L: intensity 3 (strong)) in breast cancer. Immunohistochemistry was performed according to standard protocols as described in Materials and Methods.

Figure 2

Figure 2

Relapses over time related with expression of MIC-AB (A), ULBP-1 (B), ULBP-2 (C), ULBP-3 (D), ULBP-4 (E), and ULBP-5 (F). X-axis represents patient follow-up in years; Y-axis represents cumulative relapses in %. Log-rank p-values are shown in each graph. Only expression of MIC-AB and ULBP-2 resulted in statistically significantly favorable relapse-free period (RFP).

Figure 3

Figure 3

Relapses over time related with combined expression of MIC-AB and ULBP-2. X-axis represents patient follow-up in years; Y-axis represents cumulative relapses in %. Log-rank p-values are shown in the graph. Combined low expression of MIC-AB and ULBP-2 resulted in the worst outcome of patients concerning relapse-free period (RFP); while combined high expression of both ligands resulted in the most favorable outcome of patients.

Figure 4

Figure 4

Relapses over time related with combined number of NKG2D ligands with high expression (A) and amount of expression of NKG2D ligands (B). (A) legends in graph show total number of NKG2D ligands with high expression; (B) legends in graph show total intensity score of all NKG2D ligand expression. X-axis represents patient follow-up in years; Y-axis represents cumulative relapses in %. Log-rank p-values are shown in the graph. No associations were found with outcome concerning RFP for either combined number of expressed (A) or combined amount of expression (B) of ligands.

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