International Immunology Advance Access originally published online on September 20, 2006
International Immunology 2006 18(11):1591-1602; doi:10.1093/intimm/dxl092
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Tumor cell expression of HLA-DM associates with a Th1 profile and predicts improved survival in breast carcinoma patients
1 Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada
2 Department of Pathology, Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada
3 Division of Community Health, Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada
4 Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Correspondence to: S. Drover; E-mail: sdrover{at}mun.ca
Studies aimed at elucidating the immunological and prognostic significance of HLA-DR expression on breast carcinoma cells have yielded contradictory results. To expand on previous studies, we have investigated the associations of tumor cell expression of HLA-DR and its related co-chaperones, invariant chain (Ii) and HLA-DM, with infiltrating inflammatory cells, in situ cytokine mRNA levels and prognosis and outcome in 112 breast carcinoma patients with a median follow-up of 59 months. While the majority of HLA-DR+ tumors co-express Ii, only a minority express HLA-DM. Tumor cell expression of HLA-DR and co-chaperones positively associated with both infiltrating CD4+ and CD8+ T-cell subsets (P < 0.01). Expression of HLA-DR and Ii associated with decreased estrogen receptor alpha levels and younger age at diagnosis, suggesting a role for hormones in the control of HLA class II expression in breast carcinoma. Patients with DR+Ii+DM– tumors had markedly decreased recurrence-free and disease-specific survival as compared with patients with DR+Ii+DM+ tumors (P < 0.05) and HLA-DR/co-chaperone expression was an independent predictor of survival by multivariate Cox regression analysis, controlling for standard prognostic indicators. Tumors that co-express HLA-DR, Ii and HLA-DM have increased levels of IFN-
, IL-2 and IL-12 mRNA, suggesting improved survival of patients with DR+Ii+DM+ tumors may be attributable to Th1-dominated immunity. We conclude that expression of determinants of the immune response by tumor cells may influence breast tumor progression and patient outcome.
Keywords: breast cancer, cytokines, HLA class II co-chaperones, prognostic factors, tumor infiltrating cells