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Open Access Research article

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

Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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.

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