Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer

• Published in: International journal of cancer 2005-02, Vol.113 (4), p.605-610
• Main Authors: Romero, Jose María, Jiménez, Pilar, Cabrera, Teresa, Cózar, José Manuel, Pedrinaci, Susana, Tallada, Miguel, Garrido, Federico, Ruiz-Cabello, Francisco
• Format: Article
• Language: English
• Subjects: Antigen Presentation; Antiporters - metabolism; ATP-Binding Cassette Sub-Family B Member 2; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 3; beta 2-Microglobulin - genetics; beta 2-Microglobulin - metabolism; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Cysteine Endopeptidases - metabolism; Down-Regulation; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humans; Immunoglobulins - metabolism; Major Histocompatibility Complex; Membrane Transport Proteins; Multienzyme Complexes - metabolism; Mutation; Proteasome Endopeptidase Complex; T-Lymphocytes, Cytotoxic; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism
• ISSN: 0020-7136

Downregulation of MHC class I expression is a widespread phenomenon used by tumor cells to escape antitumor T-cell-mediated immune responses. These alterations may play a role in the clinical course of the disease. The aim of our study was to investigate the molecular mechanism underlying the absence of HLA-class I molecule expression in bladder cancer cells. Microdissected tumor tissues were characterized by real-time quantitative PCR for the expression of HLA-ABC, beta2-microglobulin and the members of the antigen processing machinery (APM) of HLA class I molecules (LMP2, LMP7, TAP1, TAP2 and tapasin). Our results showed that irreversible HLA loss by mutations in the beta2-microglobulin gene was not the cause of low HLA class I expression in bladder cancers. In contrast, we observed a coordinated transcription downregulation of HLA-ABC and beta2-microglobulin and APM genes in microdissected tumor tissue derived from bladder carcinomas. This mechanism may represent a major factor for the downregulation of HLA class I expression and in the subsequent direct recognition of cancer cells by cytolytic T lymphocytes. Because this regulatory mechanism is frequently reversible by IFN-gamma treatment, we conclude that HLA class I expression should be a major consideration for immunotherapeutic purposes in patients with bladder cancer.