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Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients

Authors' Affiliations: Departments of ¹ Clinical Oncology and ² Surgery, Leiden University Medical Center, Leiden, the Netherlands; ³ Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center; ⁴ Department of Radiotherapy, Netherlands Cancer Institute, Amsterdam, the Netherlands; and ⁵ Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

Requests for reprints: Corrie A.M. Marijnen, Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. E-mail: C.A.M.Marijnen{at}lumc.nl.

Purpose: The development of local and distant recurrences is a major problem in the treatment of rectal cancer patients. In this study, we investigated whether epithelial human leukocyte antigen-DR (HLA-DR) expression allowed discrimination between high and low tumor recurrence rates, and analyzed the mechanism behind its expression.

Experimental Design: The role of IFN in HLA-DR expression was studied in rectal cancer cell lines and tumors by promoter-specific analyses of class II transactivator (CIITA). The predictive value of epithelial HLA-DR expression was investigated by immunohistochemical evaluation of 1,016 rectal tumors, obtained from a large prospective trial. Associations with recurrences and survival were determined by univariate and multivariate log-rank testing.

Results: HLA-DR was induced by IFN in rectal cancer cell lines. Activity of the IFN-inducible pIV-CIITA promoter correlated with epithelial HLA-DR expression in rectal tumors. Patients with HLA-DR–positive tumors developed less frequent local and distant recurrences [1.6% versus 9.1% (P = 0.0015) and 15.3% versus 29.9% (P < 0.0001), respectively, after 5 years of follow-up] and had better survival (78.6% versus 61.3%; P < 0.0001) than patients with HLA-DR–negative tumors. Epithelial HLA-DR was more often found in lower tumor-node-metastasis (TNM) stages. Next to TNM and circumferential resection margin, HLA-DR expression was independently associated with lower distant recurrence rates and prolonged survival.

Conclusions: Epithelial HLA-DR expression can be used as a marker to discriminate patients with high or low risk of developing recurrences. The possible involvement of IFN, the relationship with lower TNM stages, and the independent effect on recurrence development together suggest that the host immune response plays an important role in controlling tumor cells.