Considering that downregulation of HLA expression could represent a potential mechanism for breast carcinogenesis and metastasis, the aim of the present study was to use immunohistochemical methods to analyze the expression of HLA-Ia, HLA-DR, HLA-DQ, HLA-E, and HLA-G in invasive ductal carcinoma (IDC) of the breast and to relate this HLA profile to anatomopathological parameters. Fifty-two IDC from breast biopsies were stratified according to histological differentiation (well, moderately, and poorly differentiated) and to the presence of metastases in axillary lymph nodes. The expression of HLA molecules was assessed by immunohistochemistry, using a computer-assisted system. Overall, 31 (59.6%) out of the 52 IDC breast biopsies exhibited high expression of HLA-G, but only 14 (26.9%) showed high expression of HLA-E. A large number (41, 78.8%) of the biopsies showed low expression of HLA-Ia, while 45 (86.5%) showed high expression of HLA-DQ and 36 (69.2%) underexpressed HLA-DR. Moreover, 24 (41.2%) of 52 biopsies had both low HLA-Ia expression and high HLA-G expression, while 11 (21.2%) had low HLA-Ia expression and high HLA-E expression. These results suggest that, by different mechanisms, the downregulation of HLA-Ia, HLA-E, and HLA-DR and the upregulation of HLA-G and HLA-DQ are associated with immune response evasion and breast cancer aggressiveness. 1. Introduction Breast cancer is the commonest neoplasm and the second cause of cancer death in women worldwide. It is estimated that in the world more than one million women are diagnosed with breast cancer every year, and more than 410,000 will die from the disease, representing approximately 14% of female cancer deaths [1]. Human leukocyte antigen (HLA) class I molecules have a central role in the cell-mediated immune system, especially as antigen-presenting molecules for cytotoxic T lymphocytes (CTLs), which can recognize tumor antigenic bound peptides, presented on the cell surface with HLA class I molecules, and kill the target cell [2, 3]. HLA-I expression seems to be lost or downregulated on the tumor cell surface and this might represent a mechanism for neoplastic cells to escape from being killed by CTLs, allowing tumor dissemination and metastasis [4]. HLA class II molecules (HLA-DR and HLA-DQ) are essential for peptide presentation to T-helper lymphocytes, and their expression may be responsible for triggering the immune response. Thus, the presence of these antigens may make the tumor more immunogenic, which could lead to a favorable prognosis. However, it has been proposed that HLA-DR
References
[1]
S. S. Coughlin and D. U. Ekwueme, “Breast cancer as a global health concern,” Cancer Epidemiology, vol. 33, no. 5, pp. 315–318, 2009.
[2]
H. T. Khong and N. P. Restifo, “Natural selection of tumor variants in the generation of “tumor escape” phenotypes,” Nature Immunology, vol. 3, no. 11, pp. 999–1005, 2002.
[3]
J. Bubeník, “MHC class I down-regulation: tumour escape from immune surveillance?” International Journal of Oncology, vol. 25, no. 2, pp. 487–491, 2004.
[4]
M. P. Pistillo, G. Nicolò, S. Salvi et al., “Biochemical analysis of HLA class I subunits expression in breast cancer tissues,” Human Immunology, vol. 61, no. 4, pp. 397–407, 2000.
[5]
M. Redondo, J. García, E. Villar et al., “Major histocompatibility complex status in breast carcinogenesis and relationship to apoptosis,” Human Pathology, vol. 34, no. 12, pp. 1283–1289, 2003.
[6]
G. L. Palmisano, E. Contardi, A. Morabito, V. Gargaglione, G. B. Ferrara, and M. P. Pistillo, “HLA-E surface expression is independent of the availability of HLA class I signal sequence-derived peptides in human tumor cell lines,” Human Immunology, vol. 66, no. 1, pp. 1–12, 2005.
[7]
P. Moller, T. Mattfeldt, C. Gross et al., “Expression of HLA-A, -B, -C, -DR, -DP, -DQ, and of HLA-D-associated invariant chain (Ii) in non-neoplastic mammary epithelium fibroadenoma, adenoma, and carcinoma of the breast,” American Journal of Pathology, vol. 135, no. 1, pp. 73–83, 1989.
[8]
T. Torigoe, H. Asanuma, E. Nakazawa et al., “Establishment of a monoclonal anti-pan HLA class I antibody suitable for immunostaining of formalin-fixed tissue: unusually high frequency of down-regulation in breast cancer tissues,” Pathology International, vol. 62, no. 5, pp. 303–308, 2012.
[9]
E. M. De Kruijf, A. Sajet, J. G. H. Van Nes et al., “HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients,” Journal of Immunology, vol. 185, no. 12, pp. 7452–7459, 2010.
[10]
S. N. Georgiannos, A. Renaut, A. W. Goode, and M. Sheaff, “The immunophenotype and activation status of the lymphocytic infiltrate in human breast cancers, the role of the major histocompatibility complex in cell-mediated immune mechanisms, and their association with prognostic indicators,” Surgery, vol. 134, no. 5, pp. 827–834, 2003.
[11]
R. Ganss, B. Arnold, and G. J. H？mmerling, “Mini Review: overcoming tumor-intrinsic resistance to immune effector function,” European Journal of Immunology, vol. 34, no. 10, pp. 2635–2641, 2004.
[12]
T. D. Tlsty and P. W. Hein, “Know thy neighbor: stromal cells can contribute oncogenic signals,” Current Opinion in Genetics and Development, vol. 11, no. 1, pp. 54–59, 2001.
[13]
I. Gudmundsdóttir, J. Gunnlaugur Jónasson, H. Sigurdsson, K. Olafsdóttir, L. Tryggvadóttir, and H. M. Ogmundsdóttir, “Altered expression of HLA class I antigens in breast cancer: association with prognosis,” International Journal of Cancer, vol. 89, pp. 500–505, 2000.
[14]
A. Zia, F. W. Schildberg, and I. Funke, “MHC class I negative phenotype of disseminated tumor cells in bone marrow is associated with poor survival in R0M0 breast cancer patients,” International Journal of Cancer, vol. 93, no. 4, pp. 566–570, 2001.
[15]
J. Souen and F. M. Carvalho, “Rela？？o entre a express？o imunoistoquímica da proteína Her-2 e os estádios de canceres de mama e o status dos linfonodos,” Revista Brasileira de Mastologia, vol. 12, pp. 11–14, 2002.
[16]
D. Pardoll, “Does the immune system see tumors as foreign or self?” Annual Review of Immunology, vol. 21, pp. 807–839, 2003.
[17]
H. Y. Wang, D. A. Lee, G. Peng et al., “Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy,” Immunity, vol. 20, no. 1, pp. 107–118, 2004.
[18]
N. Garbi, B. Arnold, S. Gordon, G. J. H？mmerling, and R. Ganss, “CpG motifs as proinflammatory factors render autochthonous tumors permissive for infiltration and destruction,” Journal of Immunology, vol. 172, no. 10, pp. 5861–5869, 2004.
[19]
W. L. McGuire and G. M. Clark, “Prognostic factors and treatment decisions in axillary-node-negative breast cancer,” The New England Journal of Medicine, vol. 326, no. 26, pp. 1756–1761, 1992.
[20]
E. C. Ibrahim, N. Guerra, M.-J. T. Lacombe et al., “Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma,” Cancer Research, vol. 61, no. 18, pp. 6838–6845, 2001.
[21]
G. L. Palmisano, M. P. Pistillo, P. Fardin et al., “Analysis of HLA-G expression in breast cancer tissues,” Human Immunology, vol. 63, no. 11, pp. 969–976, 2002.
[22]
S. Aractingi, J. Kanitakis, S. Euvrard, C. Le Danff, and E. D. Carosella, “Selective expression of HLA-G in malignant and premalignant skin specimens in kidney transplant recipients,” International Journal of Cancer, vol. 106, no. 2, pp. 232–235, 2003.
[23]
J. Bukur, B. Malenica, C. Huber, and B. Seliger, “Altered expression of nonclassical hla class ib antigens in human renal cell carcinoma and its association with impaired immune response,” Human Immunology, vol. 64, no. 11, pp. 1081–1092, 2003.
[24]
J. Bukur, V. Rebmann, H. Grosse-Wilde et al., “Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma,” Cancer Research, vol. 63, no. 14, pp. 4107–4111, 2003.
[25]
C.-C. Chang, S. P. Murphy, and S. Ferrone, “Differential in vivo and in vitro HLA-G expression in melanoma cells: potential mechanisms,” Human Immunology, vol. 64, no. 11, pp. 1057–1063, 2003.
[26]
I. Algarra, A. García-Lora, T. Cabrera, F. Ruiz-Cabello, and F. Garrido, “The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape,” Cancer Immunology, Immunotherapy, vol. 53, no. 10, pp. 904–910, 2004.
[27]
E. C. Ibrahim, S. Aractingi, Y. Allory et al., “Analysis of HLA antigen expression in benign and malignant melanocytic lesions reveals that upregulation of HLA-G expression correlates with malignant transformation, high inflammatory infiltration and HLA-A1 genotype,” International Journal of Cancer, vol. 108, no. 2, pp. 243–250, 2004.
[28]
B. Davidson, M. B. Elstrand, M. T. McMaster et al., “HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma,” Gynecologic Oncology, vol. 96, no. 1, pp. 42–47, 2005.
[29]
N. Dutta, D. Majumder, A. Gupta, D. N. G. Mazumder, and S. Banerjee, “Analysis of human lymphocyte antigen class I expression in gastric cancer by reverse transcriptase-polymerase chain reaction,” Human Immunology, vol. 66, no. 2, pp. 164–169, 2005.
[30]
D. E. Hansel, A. Rahman, R. E. Wilentz et al., “HLA-G upregulation in pre-malignant and malignant lesions of the gastrointestinal tract,” International Journal of Gastrointestinal Cancer, vol. 35, no. 1, pp. 15–23, 2005.
[31]
G. Mouillot, C. Marcou, P. Rousseau, N. Rouas-Freiss, E. D. Carosella, and P. Moreau, “HLA-G gene activation in tumor cells involves cis-acting epigenetic changes,” International Journal of Cancer, vol. 113, no. 6, pp. 928–936, 2005.
[32]
P. L. Bouteiller and A. Blaschitz, “The functionality of HLA-G is emerging,” Immunological Reviews, vol. 167, pp. 233–244, 1999.
[33]
M. Urosevic, M. O. Kurrer, J. Kamarashev et al., “Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production,” American Journal of Pathology, vol. 159, no. 3, pp. 817–824, 2001.
[34]
S. Lefebvre, M. Antoine, S. Uzan et al., “Specific activation of the non-classical class I histocompatibility HLA-G antigen and expression of the ILT2 inhibitory receptor in human breast cancer,” Journal of Pathology, vol. 196, no. 3, pp. 266–274, 2002.
[35]
R. Marín, F. Ruiz-Cabello, S. Pedrinaci et al., “Analysis of HLA-E expression in human tumors,” Immunogenetics, vol. 54, no. 11, pp. 767–775, 2003.
[36]
P. Tomasec, V. Braud, M. Rickards et al., “Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovírusgpUL40,” Science, vol. 287, pp. 1031–1033, 2000.
[37]
F. Garrido, F. Ruiz-Cabello, T. Cabrera et al., “Implications for immunosurveillance of altered HLA class I phenotypes in human tumours,” Immunology Today, vol. 18, no. 2, pp. 89–95, 1997.
[38]
R. H. Hughes, M. Norval, and S. E. M. Howie, “Expression of major histocompatibility class II antigens by Langerhans' cells in cervical intraepithelial neoplasia,” Journal of Clinical Pathology, vol. 41, no. 3, pp. 253–259, 1988.
[39]
M. E. F. Smith, C. S. Holgate, J. M. S. Williamson, I. Grigor, P. Quirke, and C. C. Bird, “Major histocompatibility complex class II antigen expression in B and T cell non-Hodgkin's lymphoma,” Journal of Clinical Pathology, vol. 40, pp. 34–41, 1986.
[40]
R. L. Elliott, X. P. Jiang, J. T. Phillips, B. G. Barnett, and J. F. Head, “Human leukocyte antigen G expression in breast cancer: role in immunosuppression,” Cancer Biotherapy and Radiopharmaceuticals, vol. 26, no. 2, pp. 153–157, 2011.
[41]
R. Dent, M. Trudeau, K. I. Pritchard et al., “Triple-negative breast cancer: clinical features and patterns of recurrence,” Clinical Cancer Research, vol. 13, no. 15, pp. 4429–4434, 2007.
[42]
L. A. Carey, E. C. Dees, L. Sawyer et al., “The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes,” Clinical Cancer Research, vol. 13, no. 8, pp. 2329–2334, 2007.
[43]
P. K. Shetty, S. I. Thamake, S. Biswas, S. L. Johansson, and J. K. Vishwanatha, “Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer,” PLoS ONE, vol. 7, no. 9, Article ID e44299, 2012.
