Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma |
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Authors: | Akash M. Mehta Ekaterina S. Jordanova Gemma G. Kenter Soldano Ferrone Gert- Jan Fleuren |
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Affiliation: | (1) Department of Pathology, Leiden University Medical Centre, P1-40, L1-Q, 2333 ZA Leiden, The Netherlands;(2) Department of Gynaecology, Leiden University Medical Centre, Leiden, The Netherlands;(3) Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA |
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Abstract: | HLA class I loss is a significant mechanism of immune evasion by cervical carcinoma, interfering with the development of immunotherapies and cancer vaccines. We report the systematic investigation of HLA class I and antigen processing machinery component expression and association with clinical outcome. A tissue microarray containing carcinoma lesions from 109 cervical carcinoma patients was stained for HLA class I heavy chains, β2-microglobulin, LMP2, LMP7, LMP10, TAP1, TAP2, ERAP1, tapasin, calreticulin, calnexin and ERp57. A novel staining evaluation method was used to ensure optimal accuracy and reliability of expression data, which were correlated with known clinicopathological parameters. Partial HLA class I loss was significantly associated with decreased 5-years overall survival (61% vs. 83% for normal expression; P < 0.05) and was associated with decreased 5-years disease-free survival (DFS) (65% vs. 82% for normal expression; P = 0.05). All APM components except LMP10, calnexin and calreticulin were down-regulated in a substantial number of cases and, except ERAP1, correlated significantly with HLA class I down-regulation. LMP7, TAP1 and ERAP1 loss was significantly associated with decreased overall and (except LMP7) DFS (P < 0.05 and 0.005, respectively). ERAP1 down-regulation was an independent predictor for worse overall and DFS in multivariate analysis (HR 3.08; P < 0.05 and HR 2.84; P < 0.05, respectively). HLA class I and APM component down-regulation occur frequently in cervical carcinoma, while peptide repertoire alterations due to ERAP1 loss are a major contributing factor to tumour progression and mortality. |
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Keywords: | Antigen processing machinery ERAP1 Cervical carcinoma |
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