Abstract
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.
We thank T. C. Wu for providing the TC-1 cell line, M. Smahel for providing the TC-1/D11 and TC-1/A9 cell lines, T. C. Thompson for providing the LMD cell line, Andy Johnson for assistance with the flow cytometry analysis, Karen Chang and Shaun Sanders for technical assistance, and Karl-Erik Hellstrom, John Schrader, Tim Vitalis, and Kyung Bok Choi for their helpful suggestions and comments.
This work was supported by grants from Canadian Institutes of Health Research, National Cancer Institute of Canada and the Prostate Cancer Research Foundation of Canada. A.F.S was supported by the William and Dorothy Gilbert Graduate Scholarship in Biomedical Sciences. R.P.S. was supported by the Natural Sciences and Engineering Research Council of Canada and the Michael Smith Foundation for Health Research.