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Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma

โœ Scribed by Akash M. Mehta; Ekaterina S. Jordanova; Gemma G. Kenter; Soldano Ferrone; Gert- Jan Fleuren


Publisher
Springer-Verlag
Year
2007
Tongue
English
Weight
477 KB
Volume
57
Category
Article
ISSN
0340-7004

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โœฆ Synopsis


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, ฮฒ~2~-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; Pย <ย 0.05) and was associated with decreased 5-years disease-free survival (DFS) (65% vs. 82% for normal expression; Pย =ย 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 (Pย <ย 0.05 and 0.005, respectively). ERAP1 down-regulation was an independent predictor for worse overall and DFS in multivariate analysis (HR 3.08; Pย <ย 0.05 and HR 2.84; Pย <ย 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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