title: Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma.
abstract: Peptides derived from melanocyte differentiation antigens have been identified as targets for MHC class I-restricted cytolytic T lymphocytes (CTLs) in human melanoma Regression of antigen-expressing tumors as well as selection of antigen-loss variants in the presence of antigen-specific CTLs have previously been reported. In the present study, we determined the expression of the melanocyte differentiation antigens Melan A/MART-1 and tyrosinase by mRNA analysis and by immunohistochemical staining with the monoclonal antibodies (MAbs) A103 and T311. Co-expression of Melan A/MART-1 and tyrosinase was detected by both methods in 18/20 melanomas tested. However, immunohistochemistry provided additional information on intensity and microheterogeneity of antigen expression that cannot be detected by mRNA analysis as a molecular basis for the escape from CTL recognition of antigen-negative tumor cells. Comparative analysis of repeated biopsies of metastatic lesions in 5 HLA-A2+ patients showed a gradual loss of Melan A/MART-1 expression in 4/5 and of tyrosinase in 2/5 samples in association with tumor progression. However, 3 of these patients had growing antigen-positive tumors in the presence of antigen-specific CTLs. This led us to assess the expression of MHC class I, the essential restriction element for CTL recognition, and of HLA-A2. We found an unexpectedly high frequency of MHC class I-negative tumors (9/20). Loss of MHC class I expression was detected in 3/5 progressive tumors and isolated loss of HLA-A2 in 1/5 tumors. Our results suggest that strategies enhancing the expression of MHC class I and tumor-associated antigens need to be considered in attempts at making vaccination more effective.
authors.affiliation: Medical Clinic, Hematology/Oncology, Nordwest Hospital, Frankfurt am Main, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Jäger
authors.forename: M
authors.initials: M
authors.lastname: Ringhoffer
authors.forename: M
authors.initials: M
authors.lastname: Altmannsberger
authors.forename: M
authors.initials: M
authors.lastname: Arand
authors.forename: J
authors.initials: J
authors.lastname: Karbach
authors.forename: D
authors.initials: D
authors.lastname: Jäger
authors.forename: F
authors.initials: F
authors.lastname: Oesch
authors.forename: A
authors.initials: A
authors.lastname: Knuth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D001706:Biopsy; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005805:Genes, MHC Class I / Q000502:physiology*; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism; D008207:Lymphatic Metastasis; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D017931:DNA Primers; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014442:Monophenol Monooxygenase