CONSTITUTIVE TRANSDUCTION OF PEPTIDE TRANSPORTER AND HLA GENES RESTORES ANTIGEN-PROCESSING FUNCTION AND CYTOTOXIC T-CELL-MEDIATED IMMUNE RECOGNITION OF HUMAN-MELANOMA CELLS

zPotentiation of immunogenicity of malignant cells by gene transductio n provides a unique opportunity for immune targeting of human cancers in vivo. This approach is undoubtedly influenced by the ability of the malignant cells to process and present endogenously target epitopes o n their cell surface for immune recognition by cytotoxic T lymphocytes (CTLs). In the present study, we have investigated potential immune-r esistance pathways in human malignant melanoma by analyzing the major histocompatibility complex (MHC) gene expression and function in a pan el of tumour cell lines. Our analysis showed that a large proportion o f these cell lines consistently display a functional defect in the end ogenous processing of CTL epitopes and are recognised poorly by specif ic T cells in spite of high levels of target antigen expression in the tumour cells. Molecular characterisation of this defect revealed that tumour cells under-expressed peptide transporters and surface-assembl ed MHC class I molecules, which constitute essential components of the class I processing pathway. Induction of peptide transporter and surf ace class I following treatment of these tumour cells with interferon gamma (IFN-gamma) suggested a transcriptional defect in the expression of antigen-processing genes. Endogenous processing function in these tumour cells was restored completely following simultaneous transducti on of cells with peptide transporter and HLA class I genes. Our findin gs, provide a rationale for focussing on strategies designed to improv e antigen-processing function in tumour cells and, thus, may strongly influence future strategies for melanoma-specific immunotherapy. (C) 1 998 Wiley-Liss, Inc.