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 IFNg in HLA-DR expression was studied in rectal cancer cell lines and tumors by promoter-specific analyses of class II

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... or (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 IFNg in rectal cancer cell lines. Activity of the IFNg-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 followup] and had better survival (78.6% versus 61.3%; P < 0.0001) than patients with HLA-DRn egative 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 IFNg, the relationship with lowerTNM stages, and the independent effect on recurrence development together suggest that the host immune response plays an important role in controlling tumor cells.