title: Epithelial human leukocyte antigen-DR expression predicts reduced recurrence rates and prolonged survival in rectal cancer patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The role of IFNgamma 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 IFNgamma in rectal cancer cell lines. Activity of the IFNgamma-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 IFNgamma, 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.
authors.affiliation: Department of Clinical Oncology and Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Elza C
authors.initials: EC
authors.lastname: de Bruin
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: J Han J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Corrie A M
authors.initials: CA
authors.lastname: Marijnen
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
mesh_terms: D015153:Blotting, Western; D002986:Clinical Trials as Topic; D005260:Female; D006684:HLA-DR Antigens / Q000096:biosynthesis*; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D006684:HLA-DR Antigens; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D007371:Interferon-gamma