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Prognostic value of HLA class I, HLA-E, HLA-G and Tregs in rectal cancer: a retrospective cohort study

Marlies S Reimers1, Charla C Engels1, Hein Putter2, Hans Morreau3, 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

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BMC Cancer 2014, 14:486  doi:10.1186/1471-2407-14-486

Published: 5 July 2014



Evasion of immune surveillance and suppression of the immune system are important hallmarks of tumorigenesis. The goal of this study was to establish distinct patterns that reflect a rectal tumors’ immune-phenotype and to determine their relation to patient outcome.


The study population consisted of 495 Stage I-IV non-preoperatively treated rectal cancer patients of which a tissue micro array (TMA) was available. Sections of this TMA were immunohistochemically stained and quantified for presence of Foxp3+ cells (Tregs) and tumor expression of HLA Class I and non-classical HLA-E and HLA-G. All markers were, separate and combined, analyzed for clinical prognostic value.


Expression of HLA class I (DFS HR 0.637 (0.458-0.886), p = 0.013), Foxp3+ infiltration above median (OS HR 0.637 (0.500-0.813), p < 0.001 and DFS HR 0.624 (0.491-0.793), p < 0.001) and expression of HLA-G (DFS HR 0.753 (0.574-0.989), p = 0.042) were related to a better clinical prognosis. When these markers were combined, patients with 2 or 3 markers associated with poor prognosis (loss of HLA Class I, Foxp3+ below median, and weak HLA-G expression), showed a significantly worse survival (OS and DFS p < 0.001). This immune-phenotype was an independent predictor for DFS (HR 1.56 (1.14-2.14), p = 0.019).


In conclusion, rectal tumors showing loss of HLA class I expression, Foxp3+ infiltration below median and weak HLA-G expression were related to a worse OS and DFS. Combining these immune markers lead to the creation of tumor immune-phenotypes , which related to patient outcome and were significant independent clinical prognostic markers in rectal cancer.

Rectum; Rectal cancer; Immune surveillance; HLA Class I expression; Foxp3+ regulatory T cells; HLA-E; HLA-G; Outcome