Induction of MHC class I molecule cell surface expression and epigenetic activation of antigen-processing machinery components in a murine model for human papilloma virus 16-associated tumours.
Epigenetic events play an important role in tumour progression and also contribute to escape of the tumour from immune surveillance. In this study, we investigated the up-regulation of major histocompatibility complex (MHC) class I surface expression on tumour cells by epigenetic mechanisms using a murine tumour cell line expressing human E6 and E7 human papilloma virus 16 (HPV16) oncogenes and deficient in MHC class I expression, as a result of impaired antigen-presenting machinery (APM). Treatment of the cells with the histone deacetylase inhibitor Trichostatin A, either alone or in combination with the DNA demethylating agent 5-azacytidine, induced surface re-expression of MHC class I molecules. Consequently, the treated cells became susceptible to lysis by specific cytotoxic T lymphocytes. Further analysis revealed that epigenetic induction of MHC class I surface expression was associated with the up-regulation of APM genes [transporter associated with antigen processing 1 (TAP-1), TAP-2, low-molecular-mass protein 2 (LMP-2) and LMP-7]. The results demonstrate that expression of the genes involved in APM are modulated by epigenetic mechanisms and suggest that agents modifying DNA methylation and/or histone acetylation have the potential to change the effectiveness of antitumour immune responses and therapeutically may have an impact on immunological output.
Manning
Jasper
J
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Indrova
Marie
M
Lubyova
Barbora
B
Pribylova
Hana
H
Bieblova
Jana
J
Hejnar
Jiri
J
Simova
Jana
J
Jandlova
Tana
T
Bubenik
Jan
J
Reinis
Milan
M
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000276:immunology*; D005805:Genes, MHC Class I; D006657:Histones / Q000378:metabolism; D052162:Human papillomavirus 16; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000821:virology; D030361:Papillomavirus Infections / Q000150:complications*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D001374:Azacitidine