title: Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma.
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, beta(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; 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.
authors.affiliation: Department of Pathology, Leiden University Medical Centre, P1-40, L1-Q, 2333 ZA Leiden, The Netherlands.
authors.forename: Akash M
authors.initials: AM
authors.lastname: Mehta
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Gert-Jan
authors.initials: GJ
authors.lastname: Fleuren
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000626:Aminopeptidases / Q000378:metabolism; D017951:Antigen Presentation / Q000276:immunology*; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D011379:Prognosis; D046888:Tissue Array Analysis; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D015778:Minor Histocompatibility Antigens; C073119:TAP1 protein, human; D000626:Aminopeptidases; C464841:ERAP1 protein, human