Abstract
Alterations in HLA class I antigen expression have been frequently described in different epithelial tumors and are thought to favor tumor immune escape from T lymphocyte recognition. Multiple molecular mechanisms are responsible for these altered HLA class I tumor phenotypes. Some are structural defects that produce unresponsiveness to treatment with interferons. Others include alterations in regulatory mechanisms that can be switched on by treatment of tumor cells with different cytokines. One important mechanism belonging to the first group is loss of heterozygosity (LOH) at chromosome region 6p21.3, which can lead to HLA haplotype loss. In this investigation, the frequency of LOH at 6p21 chromosome region was studied in 69 bladder carcinomas. Short tandem repeat analysis showed that 35% of cases had LOH in this chromosome region. By considering these results together with immunohistological findings previously published by our group, we identified a distribution pattern of HLA class I altered phenotypes in bladder cancer. The most frequently altered phenotype in bladder carcinomas was total loss of HLA class I expression (17 cases, 25%), followed by phenotype II associated with HLA haplotype loss (12 cases, 17.5%), and HLA allelic loss (ten cases, 14.5%). Nine cases (13%) were classified as having a compound phenotype, five cases (7%) as having HLA locus loss, and in 16 cases (23%) no alteration in HLA expression was detected. An important conclusion of this report is that a combination of different molecular and immunohistological techniques is required to precisely define which HLA alleles are lost during tumor progression and to characterize the underlying mechanisms of these losses. These studies should be performed when a cancer patient is to be included in an immunotherapy protocol that aims to stimulate different immune effector mechanisms.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- STR:
-
Short tandem repeats
- LOH:
-
Loss of heterozygosity
- TCC:
-
Transitional cell carcinomas
References
Algarra I, Collado A, Garrido F (1997) Altered MHC class I antigens in tumors. Int J Clin Lab Res 27:95–102
Bar-Haim E, Paz A, Machlenkin A, Hazzan D, Tirosh B, Carmon L, Brenner B, Vadai E, Mor O, Stein A, Lemonnier FA, Tzehoval E, Eisenbach L (2004) MAGE-A8 overexpression in transitional cell carcinoma of the bladder: identification of two tumour-associated antigen peptides. Br J Cancer 91:398–407
Bruch J, Schulz WA, Haussler J, Melzner I, Bruderlein S, Moller P, Kemmerling R, Vogel W, Hameister H (2000) Delineation of the 6p22 amplification unit in urinary bladder carcinoma cell lines. Cancer Res 60:4526–4530
Cabrera T, Angustias Fernandez M, Sierra A, Garrido A, Herruzo A, Escobedo A, Fabra A, Garrido F (1996) High frequency of altered HLA class I phenotypes in invasive breast carcinomas. Hum Immunol 50:127–134
Cabrera T, Pedrajas G, Cozar JM, Garrido A, Vicente J, Tallada M, Garrido F (2003) HLA class I expression in bladder carcinomas. Tissue Antigens 62:324–327
Fruh K, Yang Y (1999) Antigen presentation by MHC class I and its regulation by interferon gamma. Curr Opin Immunol 11:76–81
Garcia-Lora A, Algarra I, Garrido F (2003) MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 195:346–355
Garrido F, Algarra I (2001) MHC antigens and tumor escape from immune surveillance. Adv Cancer Res 83:117–158
Garrido F, Ruiz-Cabello F, Cabrera T, Perez-Villar JJ, Lopez-Botet M, Duggan-Keen M, Stern PL (1997) Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today 18:89–95
Knowles MA, Elder PA, Williamson M, Cairns JP, Shaw ME, Law MG (1994) Allelotype of human bladder cancer. Cancer Res 54:531–538
Koene GJ, Arts-Hilkes YH, van Dijk AJ, van der Ven KJ, Slootweg PJ, de Weger RA, Tilanus MG (2004) High level of aneuploidy of chromosome 6 by FISH analysis of head and neck squamous cell carcinoma: limited applicability of LOH analysis to define HLA loss. Hum Immunol 65:1455–1462
Levin I, Klein T, Goldstein J, Kuperman O, Kanetti J, Klein B (1991) Expression of class I histocompatibility antigens in transitional cell carcinoma of the urinary bladder in relation to survival. Cancer 68:2591–2594
Madjd Z, Spendlove I, Pinder SE, Ellis IO, Durrant LG (2005) Total loss of MHC class I is an independent indicator of good prognosis in breast cancer. Int J Cancer 117(2):248–255
Maleno I, Lopez-Nevot MA, Cabrera T, Salinero J, Garrido F (2002) Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunol. Immunother 51:389–396
Maleno I, Cabrera CM, Cabrera T, Paco L, Lopez-Nevot MA, Collado A, Ferron A, Garrido F (2004a) Distribution of HLA class I altered phenotypes in colorectal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Immunogenetics 56:244–253
Maleno I, Lopez Nevot MA, Seliger B, Garrido F (2004b) Low frequency of HLA haplotype loss associated with loss of heterozygocity in chromosome region 6p21 in clear renal cell carcinomas. Int J Cancer 109:636–638
Marin R, Ruiz-Cabello F, Pedrinaci S, Mendez R, Jimenez P, Geraghty DE, Garrido F (2003) Analysis of HLA-E expression in human tumors. Immunogenetics 54:767–775
Nishiyama T, Tachibana M, Horiguchi Y, Nakamura K, Ikeda Y, Takesako K, Murai M (2001) Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24-specific MAGE-3 peptide. Clin Cancer Res 7:23–31
Olumi AF, Tsai YC, Nichols PW, Skinner DG, Cain DR, Bender LI, Jones PA (1990) Allelic loss of chromosome 17p distinguishes high grade from low grade transitional cell carcinomas of the bladder. Cancer Res 50:7081–7083
Patard JJ, Brasseur F, Gil-Diez S, Radvanyi F, Marchand M, Francois P, Abi-Aad A, Van Cangh P, Abbou CC, Chopin D et al (1995) Expression of MAGE genes in transitional-cell carcinomas of the urinary bladder. Int J Cancer 64:60–64
Presti JC Jr, Reuter VE, Galan T, Fair WR, Cordon-Cardo C (1991) Molecular genetic alterations in superficial and locally advanced human bladder cancer. Cancer Res 51:5405–5409
Ramal LM, Feenstra M, van der Zwan AW, Collado A, Lopez-Nevot MA, Tilanus M, Garrido F (2000a) Criteria to define HLA haplotype loss in human solid tumors. Tissue Antigens 55:443–448
Ramal LM, Maleno I, Cabrera T, Collado A, Ferron A, Lopez-Nevot MA, Garrido F (2000b) Molecular strategies to define HLA haplotype loss in microdissected tumor cells. Hum Immunol 61:1001–1012
Raval A, Puri N, Rath PC, Saxena RK (1998) Cytokine regulation of expression of class I MHC antigens. Exp Mol Med 30:1–13
Richter J, Beffa L, Wagner U, Schraml P, Gasser TC, Moch H, Mihatsch MJ, Sauter G (1998) Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization. Am J Pathol 153:1615–1621
Richter J, Jiang F, Gorog JP, Sartorius G, Egenter C, Gasser TC, Moch H, Mihatsch MJ, Sauter G (1997) Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res 57:2860–2864
Rivoltini L, Carrabba M, Huber V, Castelli C, Novellino L, Dalerba P, Mortarini R, Arancia G, Anichini A, Fais S, Parmiani G (2002) Immunity to cancer: attack and escape in T lymphocyte-tumor cell interaction. Immunol Rev 188:97–113
Romero JM, Jimenez P, Cabrera T, Cozar JM, Pedrinaci S, Tallada M, Garrido F, Ruiz-Cabello F (2005) Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer. Int J Cancer 113:605–610
Ruppert JM, Tokino K, Sidransky D (1993) Evidence for two bladder cancer suppressor loci on human chromosome 9. Cancer Res 53:5093–5095
Sandberg AA, Berger CS (1994) Review of chromosome studies in urological tumors. II. Cytogenetics and molecular genetics of bladder cancer. J Urol 151:545–560
Sharma P, Gnjatic S, Jungbluth AA, Williamson B, Herr H, Stockert E, Dalbagni G, Donat SM, Reuter VE, Santiago D, Chen YT, Bajorin DF, Old LJ (2003) Frequency of NY-ESO-1 and LAGE-1 expression in bladder cancer and evidence of a new NY-ESO-1 T-cell epitope in a patient with bladder cancer. Cancer Immun 3:19
Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD (2004) Intravesical bacillus Calmette–Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int 93:485–490
Stadler WM, Steinberg G, Yang X, Hagos F, Turner C, Olopade OI (2001) Alterations of the 9p21 and 9q33 chromosomal bands in clinical bladder cancer specimens by fluorescence in situ hybridization. Clin Cancer Res 7:1676–1682
Acknowledgements
This study was supported by the Instituto de Salud Carlos III-Red de centros Cancer-RTICCC contract n° CO3/10, Fondo de Investigaciones Sanitarias (FIS) PI 03/0977, Consejeria de Salud, Junta de Andalucia by Plan Andaluz de Investigación (PAI), and by EU project ENACT contract n° 503306.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Maleno, I., Romero, J.M., Cabrera, T. et al. LOH at 6p21.3 region and HLA class altered phenotypes in bladder carcinomas. Immunogenetics 58, 503–510 (2006). https://doi.org/10.1007/s00251-006-0111-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-006-0111-8