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, b 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 downregulation occur frequently in cervical carcinoma, while peptide repertoire alterations due to ERAP1 loss are a major contributing factor to tumour progression and mortality.

Immunogenic death of colon cancer cells treated with oxaliplatin

“…In this context, it seems intriguing that reduced calreticulin expression constitutes a negative prognostic/predictive feature of colon cancers (Toquet et al, 2007). Reduced calreticulin expression also has a negative impact on neuroblastoma (Hsu et al, 2005), cervical carcinoma (Mehta et al, 2008), as well as on follicular thyroid carcinoma (Netea-Maier et al, 2008). Hence, it will be important to investigate whether CRT affects the immunogenicity of such tumors beyond its role in contributing to optimal peptide loading into major histocompatibility complex class I antigen (Wright et al, 2004;Zhang and Williams, 2006).…”

Overexpression of β2-microglobulin is associated with poor survival in patients with oral cavity squamous cell carcinoma and contributes to oral cancer cell migration and invasion

“…Levels À and þ were defined as weak b2M expression, whereas levels þ þ and þ þ þ were defined as strong expression. A sample was considered positive if 1 -5% of the tumour cells showed positive staining as described (Mehta et al, 2008). Those samples in which positive staining were detected in over 50% of the tumour cells were considered strongly positive for b2M.…”

PRAME and HLA Class I expression patterns make synovial sarcoma a suitable target for PRAME specific T-cell receptor gene therapy

“…31 Secondary visualization was performed using a 3,3ʹ-Diaminobenzidine(DAB) based standard laboratory procedure that was described before. 19 Endothelial cells from blood vessels within the tumor served as a positive control for antibody staining.…”