Epigenetic control of the immune escape mechanisms in malignant carcinomas.
Downregulation of the transporter associated with antigen processing 1 (TAP-1) has been observed in many tumors and is closely associated with tumor immunoevasion mechanisms, growth, and metastatic ability. The molecular mechanisms underlying the relatively low level of transcription of the tap-1 gene in cancer cells are largely unexplained. In this study, we tested the hypothesis that epigenetic regulation plays a fundamental role in controlling tumor antigen processing and immune escape mechanisms. We found that the lack of TAP-1 transcription in TAP-deficient cells correlated with low levels of recruitment of the histone acetyltransferase, CBP, to the TAP-1 promoter. This results in lower levels of histone H3 acetylation at the TAP-1 promoter, leading to a decrease in accessibility of the RNA polymerase II complex to the TAP-1 promoter. These observations suggest that CBP-mediated histone H3 acetylation normally relaxes the chromatin structure around the TAP-1 promoter region, allowing transcription. In addition, we found a hitherto-unknown mechanism wherein interferon gamma up-regulates TAP-1 expression by increasing histone H3 acetylation at the TAP-1 promoter locus. These findings lie at the heart of understanding immune escape mechanisms in tumors and suggest that the reversal of epigenetic codes may provide novel immunotherapeutic paradigms for intervention in cancer.
Setiadi
A Francesca
AF
Biomedical Research Centre, Vancouver, British Columbia V6T 1Z3, Canada.
David
Muriel D
MD
Seipp
Robyn P
RP
Hartikainen
Jennifer A
JA
Gopaul
Rayshad
R
Jefferies
Wilfred A
WA
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005805:Genes, MHC Class I; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008285:Major Histocompatibility Complex; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006657:Histones; D011993:Recombinant Fusion Proteins; C073119:TAP1 protein, human; D007371:Interferon-gamma; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D012319:RNA Polymerase II