Oldford Sharon A, Robb J Desmond, Codner Dianne, Gadag Veeresh, Watson Peter H, Drover Sheila
Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada.
Int Immunol. 2006 Nov;18(11):1591-602. doi: 10.1093/intimm/dxl092. Epub 2006 Sep 20.
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-gamma, 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.
旨在阐明乳腺癌细胞上HLA - DR表达的免疫学及预后意义的研究得出了相互矛盾的结果。为了拓展先前的研究，我们调查了112例乳腺癌患者肿瘤细胞HLA - DR及其相关共伴侣分子、恒定链（Ii）和HLA - DM的表达与浸润性炎症细胞、原位细胞因子mRNA水平以及预后和结局的关系，这些患者的中位随访时间为59个月。虽然大多数HLA - DR阳性肿瘤共表达Ii，但只有少数表达HLA - DM。肿瘤细胞HLA - DR和共伴侣分子的表达与浸润性CD4⁺和CD8⁺ T细胞亚群均呈正相关（P < 0.01）。HLA - DR和Ii的表达与雌激素受体α水平降低及诊断时年龄较轻相关，提示激素在乳腺癌HLA II类表达调控中起作用。与DR⁺Ii⁺DM⁺肿瘤患者相比，DR⁺Ii⁺DM⁻肿瘤患者的无复发生存期和疾病特异性生存期显著降低（P < 0.05），并且通过多变量Cox回归分析，在控制标准预后指标的情况下，HLA - DR/共伴侣分子表达是生存的独立预测因素。共表达HLA - DR、Ii和HLA - DM的肿瘤中IFN - γ、IL - 2和IL - 12 mRNA水平升高，提示DR⁺Ii⁺DM⁺肿瘤患者生存改善可能归因于以Th1为主导的免疫反应。我们得出结论，肿瘤细胞免疫反应决定因素的表达可能影响乳腺肿瘤进展和患者结局。
