Downregulation of MHC class I expression on tumour cells, a common mechanism by which tumour cells can escape from specific immune responses, can be associated with coordinated silencing of antigen-presenting machinery genes. The expression of these genes can be restored by IFNγ. In this study we documented association of DNA demethylation of selected antigen-presenting machinery genes located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells in several MHC class I-deficient murine tumour cell lines (TC-1/A9, TRAMP-C2, MK16 and MC15). Our data also documented higher methylation levels in these genes in TC-1/A9 cells, as compared to their parental MHC class I-positive TC-1 cells. IFNγ-mediated DNA demethylation was relatively fast in comparison with demethylation induced by DNA methyltransferase inhibitor 5-azacytidine, and associated with increased histone H3 acetylation in the promoter regions of APM genes. Comparative transcriptome analysis in distinct MHC class I-deficient cell lines upon their treatment with either IFNγ or epigenetic agents revealed that a set of genes, significantly enriched for the antigen presentation pathway, was regulated in the same manner. Our data demonstrate that IFNγ acts as an epigenetic modifier when upregulating the expression of antigen-presenting machinery genes.

• MeSH
• Down-Regulation MeSH
• Epigenesis, Genetic MeSH
• Fibrosarcoma genetics   immunology   metabolism   MeSH
• Genes, MHC Class I * MeSH
• Interferon-gamma genetics   immunology   metabolism   MeSH
• DNA Methylation * MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Tumor Cells, Cultured MeSH
• Antigen Presentation genetics   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Signal Transduction MeSH
• Transfection MeSH
• Up-Regulation MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Interferon-gamma MeSH

BACKGROUND: Epigenetic mechanisms have important roles in the tumour escape from immune responses, such as in MHC class I downregulation or altered expression of other components involved in antigen presentation. Chemotherapy with DNA methyltransferase inhibitors (DNMTi) can thus influence the tumour cell interactions with the immune system and their sensitivity to immunotherapy. METHODS: We evaluated the therapeutic effects of the DNMTi 5-azacytidine (5AC) against experimental MHC class I-deficient and -positive tumours. The 5AC therapy was combined with immunotherapy, using a murine model for HPV16-associated tumours. RESULTS: We have demonstrated 5AC additive effects against MHC class I-positive and -deficient tumours when combined with unmethylated CpG oligodeoxynucleotides or with IL-12-producing cellular vaccine. The efficacy of the combined chemoimmunotherapy against originally MHC class I-deficient tumours was partially dependent on the CD8(+)-mediated immune responses. Increased cell surface expression of MHC class I cell molecules, associated with upregulation of the antigen-presenting machinery-related genes, as well as of genes encoding selected components of the IFNγ-signalling pathway in tumours explanted from 5AC-treated animals, were observed. CONCLUSION: Our data suggest that chemotherapy of MHC class I-deficient tumours with 5AC combined with immunotherapy is an attractive setting in the treatment of MHC class I-deficient tumours.

• MeSH
• Azacitidine pharmacology   MeSH
• DNA Primers MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Neoplasms, Experimental drug therapy   immunology   therapy   virology   MeSH
• Immunotherapy * MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Human papillomavirus 16 isolation & purification   MeSH
• Methylation MeSH
• Histocompatibility Antigens Class I immunology   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Antimetabolites, Antineoplastic pharmacology   MeSH
• Base Sequence MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Azacitidine MeSH
• DNA Primers MeSH
• Histocompatibility Antigens Class I MeSH
• Antimetabolites, Antineoplastic MeSH