HLA‐DRB alleles are differentially expressed by tumor cells in breast carcinoma

Abstract

The biologic and prognostic significance of HLA-DR expression and T-cell infiltration in breast carcinoma are presently controversial. To test the hypothesis that these factors are influenced by particular HLA-DRB alleles, 52 breast tumor samples, composed of 26 DRB1*04 and 26 non-DRB1*04 tumors, were assessed using immunohistochemistry for expression of DR and its associated invariant chain (Ii) and for infiltrating CD3 ؉ T cells. While DR expression by tumor cells was significantly associated with T-cell infiltration, DRB1*04 tumors were more frequently DR ؉ Ii ؉ and contained smaller CD3 ؉ infiltrates than non-DRB1*04 tumors. This difference was largely attributable to DRB1*07 tumors, which were typically DR ؊ Ii ؊ , although they contained similar numbers of T cells to DR ؉ Ii ؉ tumors. Further analysis of DR ؉ tumors using allotype discriminating antibodies revealed that DRB1*04 alleles were always expressed, while non-DRB1*04 alleles were inconsistently expressed. The results of this study provide the first reported evidence that DRB alleles influence DR expression and T-cell infiltration in breast carcinoma and suggest that multiple factors contribute to DR expression. Ongoing studies aimed at elucidating the molecular and immunologic mechanisms controlling differential DR expression and implications for prognosis and outcome should further our understanding of the antitumor immune response and evasion strategies employed by tumor cells. © 2004 Wiley-Liss, Inc. Key words: HLA-DR expression; HLA-DRB alleles; T-cell infiltration; breast carcinoma; invariant chainA prerequisite for tumor eradication by CD8 ϩ cytolytic T cells is recognition of tumor antigen presented by HLA class I molecules on the tumor cells and this is reflected by the numerous studies showing loss or downregulation of HLA class I on established tumors. 1,2 Optimal antitumor immunity also requires participation of CD4 ϩ T cells, which recognize tumor peptides presented by HLA class II molecules (HLA-DR, -DP, -DQ). [3][4][5] However, the importance of HLA class II expression on breast carcinoma cells and implications for antitumor immunity are currently unclear. Unlike HLA class I, HLA class II molecules are not normally present on resting epithelial cells, although they are detected de novo in the lactating breast and in a subset of breast carcinomas. 6 They can also be induced in vitro on many cell types, including breast cancer cell lines, by interferon-␥ (IFN-␥) 7,8 and other immunomodulators, 9,10 suggesting that in situ expression on carcinoma cells may be regulated by cytokines and/or hormones. Antigen presentation by HLA class II ϩ breast cancer cells, which lack costimulatory molecules typically found on professional antigen presenting cells (APCs), could potentially induce T-cell anergy. However, reports of direct recognition of tumor cells by HLA class II-restricted CD4 ϩ T cells 11,12 suggest that HLA class II ϩ tumor cells play an important role in determining the outcome of an antitumor immune response.Studies investigating e...

CTL-Tumor Cell Interaction: The Generation of Molecular Probes of Monitoring the HLA-A*0201-HER-2/neu Peptide Complex

“…To date, IHC staining of over 1000 surgically removed breast carcinoma lesions has shown that HLA class II antigens are often up-regulated on malignant tumors of mammary epithelial cells [14,19,23,24,26,32,[112][113][114][115][116][117][118][119][120][121]. As observed in colon and cervical epithelial cells [122,123], HLA class II antigen expression does not appear to be restricted to cells which have undergone malignant transformation, since IHC analysis has also identified HLA class II antigen expression in benign mammary lesions [19,23,26,114,115].…”

“…All the studies performed have investigated HLA-DR antigen expression [14,19,23,24,26,32,[112][113][114][115][116][117][118][119][120][121]124,125], while only five have examined HLA-DP and HLA-DQ antigen expression. In all five studies, irrespective of the frequency of HLA class II antigen detection in the breast carcinoma lesions analyzed, HLA-DR antigens have been found to be more frequently expressed than HLA-DQ and DP antigens [23,32,116,124,125].…”

“…It is noteworthy that no clear relationship has been established between HLA class II antigen expression and T cell infiltration of breast carcinoma lesions [19,20,22,26,121]. An alternative and distinct mechanism underlying HLA class II antigen up-regulation on breast carcinoma cells is represented by molecular changes associated with malignant transformation of mammary epithelial cells and/or disease progression.…”

“…Furthermore, LOH of chromosome 6p is likely to play a role in the lack of HLA class II antigen expression, since this mechanism causes HLA haplotype loss in a high percentage of tumors [75] and mutations in the remaining copy of chromosome 6 would then result in lack of HLA antigen expression. The role of this combined mechanism is supported by the increased frequency of HLA class I antigen loss in HLA class II antigen negative tumors [23,121]. Defects in transcriptional regulation may also be responsible for defective HLA class II antigen expression in breast carcinoma cell lines.…”

“…However, a recent study suggests that these discrepancies may in fact be related to differences in the amount T cell tumor infiltration, since HLA-DR antigen expression was found to be associated with welldifferentiated tumors that lack a T cell infiltrate [121]. Therefore, HLA class II antigen up- ) and followi( ) in vitro tvXuop-rttov oo XsX),a ottrj IhN-y.…”