Expression of HLA class I antigens and restoration of antigen-specific ctlresponse 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 gene tic defects underlying the lack of HLA class I expression have been charact erized. Here we describe another molecular mechanism that accounts for the complete absence of HLA class I molecule expression in a tumor line (MSR3-m el) 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 an d 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.AI 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 t he first evidence that DNA hypermethylation is used by human neoplastic cel ls to switch off HLA class I genes, thus providing a new route of escape fr om immune recognition. (C) 2001 Wiley-Liss, Inc.