pregulation of human leukocyte antigen – G expression and its clinical ignificance in ductal breast cancer

Human leukocyte antigen(HLA)–G could inhibit functions of immune cells and induce regulatory T cells (Treg) and could be involved in antitumor immune responses. In the current study, HLA-G expression in 58 primary breast cancer lesions was analyzed with immunohistochemistry. Plasma soluble HLA-G was detected with enzyme-linked immunosorbent assay in 92 breast cancer patients and in 70 normal healthy donors. The proportion of CD4 CD25 FoxP3 Treg was analyzed with flow cytometry in 64 breast cancer patients and 23 normal controls. HLA-G expression was observed in 70.7% (41/58) of breast cancer lesions. LesionHLA-Gexpressionwasmore frequently observed in advanceddisease stage (I/II vs III/IV,p 0.044) and tumor grade (I/II vs III/IV, p 0.021). sHLA-G was dramatically increased in patients when compared with normal controls (median 82.19 vs 9.65 U/ml, p 0.001); The area under the receiver operating characteristic (ROC) curve for sHLA-Gwas 0.953 (95% confidence interval [CI] 0.926–0.981, p 0.001). However, sHLA-G was irrelevant to the disease stage and tumor grade. Moreover, CD4 CD25 FoxP3 Treg are markedly increased in the breast cancer patients compared with normal controls (4.46 1.36% vs 2.67 1.45%, p 0.001), and the increased frequency of Treg was strongly correlated to sHLA-G levels (R 0.582, p 0.001). Our findings indicated that HLA-G could play critical roles in the progression of breast cancer, and plasma sHLA-G levels might be a useful preoperative biomarker for diagnosis. 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. c p n e t p d H H t t m ( g A e ( t s . Introduction During tumor development, immune cells infiltrate to tumors nd make up a significant component of the multicellular cancer icroenvironment; yet the immune system often fails to prevent umor formation and progression [1]. A variety of strategies have een developed by tumor cells to avoid recognition by different inds of immune effectors. Alteration of human leukocyte antigen HLA) expression, structure, and function represents a frequent vent in cancer and serves to circumvent T-cell and natural killer NK) cell responses [2]. Other potent mechanisms, such as the resence of tolerance-promoting regulatory T cells (Tregs), would lso benefit the tumor cells escaping from antitumor immune esponses [3]. Aberrant upregulated expression of the nonclassical HLA class I ntigen human leukocyte antigen-G (HLA-G) was observed in any types of cancers [4]. However, HLA-G expression in normal issue is limited to fetal trophoblast cells, adult thymic medulla, m * Corresponding author. E-mail address: yanwhcom@yahoo.com (W.-H. Yan). 198-8859/10/$32.00 see front matter 2010 American Society for Histocompatibility oi:10.1016/j.humimm. 2010.06. 009 ornea, nail matrix, pancreatic islets, erythroid and endothelial recursors, and in mesenchymal stem cells [5–11]. An increasing umber of studies have highlighted the clinical relevance of HLA-G xpression in certain pathologic conditions, such as those relating o oncology, autoimmunity, inflammation, infection, and translantation [12]. In the context ofmalignancies, since Paul et al. [13] escribed for the first time the expression of HLA-G in melanoma, LA-G expression in situwas observed nearly in 30 types of tumors. LA-Gwas preferentially detected in the tumor tissue and rarely in he adjacent normal tissue, suggesting that it might play a role in umor growth and progression, and could be a potential diagnosis arker and immunotherapy target for cancers [14–16]. Unlike classical HLA class I antigens, four membrane-bound HLA-G1–G4) and three soluble HLA-G isoforms (HLA-G5–G7) are enerated by alternative splicing of its primary transcript [17,18]. nother soluble form of HLA-G molecule, however, could be genrated by shedding of the proteolytically cleaved surface HLA-G1 sHLA-G1). Therefore, plasma sHLA-G could derive from the secreion of soluble isoforms, especially HLA-G5, as well as from the hedding form of HLA-G1 [19]. Previous studies indicated that both embrane-bound and soluble HLA-G proteins could play profound and Immunogenetics. Published by Elsevier Inc. All rights reserved. s p N I t r u H s m c C t m b o H i