Rexpression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2'-deoxycytidine treatment.
Cell surface expression of HLA class I/peptide complexes on tumor cells is a key step in the generation of T-cell-based immune responses. Several genetic defects underlying the lack of HLA class I expression have been characterized. Here we describe another molecular mechanism that accounts for the complete absence of HLA class I molecule expression in a tumor line (MSR3-mel) derived from a melanoma patient. Hypermethylation of the MSR3-mel DNA, specifically of HLA-A and -B genes, was identified, which resulted in loss of HLA class I heavy chain transcription. Treatment of MSR3-mel cells with the demethylating agent 5'-aza-2'-deoxycytidine (DAC) allowed HLA-A and -B transcription, restoring cell surface expression of HLA class I antigens and tumor cell recognition by MAGE-specific cytotoxic T lymphocytes. The MSR3-mel line was obtained from a metastatic lesion of a nonresponding patient undergoing MAGE-3.A1 T-cell-based peptide immunotherapy. It is tempting to speculate that the hypermethylation-induced lack of HLA class I expression is the cause of the impaired response to vaccination. This study provides the first evidence that DNA hypermethylation is used by human neoplastic cells to switch off HLA class I genes, thus providing a new route of escape from immune recognition.
Serrano
A
A
Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain.
Tanzarella
S
S
Lionello
I
I
Mendez
R
R
Traversari
C
C
Ruiz-Cabello
F
F
Garrido
F
F
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D019175:DNA Methylation; D000077209:Decitabine; D018984:Epitopes, T-Lymphocyte; D005805:Genes, MHC Class I; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D000077209:Decitabine; D001374:Azacitidine