Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma.
In cervical carcinomas abnormalities in the MHC class I surface expression are a frequent event, which are often associated with the deficient expression of the peptide transporter subunit TAP1 thereby resulting in impaired T cell response. In order to understand the role of other components of the MHC class I antigen processing machinery (APM) in the immune escape, 16 surgically removed primary cervical carcinoma lesions were analyzed for their mRNA expression of the heterodimeric peptide transporter TAP, the constitutive and interferon (IFN)-gamma inducible proteasome subunits and their activators PA28alpha/beta, various chaperones as well as MHC class I antigens. High expression levels of all APM components were detected in normal cervical tissue, whereas 15/16 of cervical carcinoma lesions exhibited an impaired expression of at least one APM component, including the proteasome subunits, their activators PA28alpha/beta, the peptide transporter subunits TAP1 and TAP2, different chaperones, HLA class I heavy chains and beta2-microglobulin (beta2-m). In particular, calnexin expression was strongly downregulated in 69% of cervical cancer lesions analyzed. Such abnormalities were neither associated with a specific human papilloma virus (HPV) or HLA class I phenotype nor with tumor grading and staging. Analysis of five cervical carcinoma cell lines demonstrated a reduced MHC class I surface expression due to deficient expression and function of TAP, LMP subunits or specific HLA-alleles which could be mostly corrected by IFN-gamma treatment. The high frequency of abnormalities of APM component expression together with their potential negative influence on T cell-mediated immune recognition emphasize the need to evaluate the antigen processing pathway in cervical carcinoma patients, particularly in those selected for T-cell-based immunotherapies.
Ritz
U
U
Third Department of Internal Medicine, Johannes Gutenberg University, 55131 Mainz, Germany.
Momburg
F
F
Pilch
H
H
Huber
C
C
Maeurer
M J
MJ
Seliger
B
B
D017951:Antigen Presentation / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D005805:Genes, MHC Class I / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
D014408:Biomarkers, Tumor; D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D007371:Interferon-gamma