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.

Department of Tumour Immunology Institute of Molecular Genetics Academy of Sciences of the Czech Republic v v i Prague

Department of Viral and Cellular Genetics Institute of Molecular Genetics Academy of Sciences of the Czech Republic v v i Prague

UPMC Univ Paris 06 UMR 7211 Immunology Immunopathology Immunotherapy Paris France

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Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692. PubMed PMC

Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–1159. PubMed

Sigalotti L, Coral S, Fratta E, Lamaj E, Danielli R, Di Giacomo AM, Altomonte M, Maio M. Epigenetic modulation of solid tumors as a novel approach for cancer immunotherapy. Semin Oncol. 2005;32:473–478. PubMed

Tomasi TB, Magner WJ, Khan AN. Epigenetic regulation of immune escape genes in cancer. Cancer Immunol Immunother. 2006;55:1159–1184. PubMed PMC

Garrido F, Ruiz-Cabello F, Cabrera T, Perez-Villar JJ, Lopez-Botet M, Duggan-Keen M, Stern PL. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today. 1997;18:89–95. PubMed

Bubeník J. Tumour MHC class I downregulation and immunotherapy (Review) Oncol Rep. 2003;10:2005–2008. PubMed

Reiniš M. Immunotherapy of MHC class I-deficient tumors. Future Oncol. 2010;6:1577–1589. PubMed

Seliger B. Novel insights into the molecular mechanisms of HLA class I abnormalities. Cancer Immunol Immunother. 2012;61:249–254. PubMed PMC

Garrido F, Cabrera T, Aptsiauri N. “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy (Review) Int J Cancer. 2010;127:249–256. PubMed

Seliger B, Wollscheid U, Momburg F, Blankenstein T, Huber C. Coordinate downregulation of multiple MHC class I antigen processing genes in chemical-induced murine tumor cell lines of distinct origin. Tissue Antigens. 2000;56:327–336. PubMed

Garcia-Lora A, Martinez M, Algarra I, Gaforio JJ, Garrido F. MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components. Int J Cancer. 2003;106:521–527. PubMed

Gabathuler R, Reid G, Kolaitis G, Driscoll J, Jefferies WA. Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing. J Exp Med. 1994;180:1415–1425. PubMed PMC

Setiadi AF, David MD, Seipp RP, Hartikainen JA, Gopaul R, Jefferies WA. Epigenetic control of the immune escape mechanisms in malignant carcinomas. Mol Cell Biol. 2007;27:7886–7894. PubMed PMC

Christova R, Jones T, Wu PJ, Bolzer A, Costa-Pereira AP, Watling D, Kerr IM, Sheer D. P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFNgamma. J Cell Sci. 2007;120:3262–3270. PubMed

Manning J, Indrova M, Lubyova B, Pribylova H, Bieblova J, Hejnar J, Simova J, Jandlova T, Bubenik J, Reinis M. 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. Immunology. 2008;123:218–227. PubMed PMC

Setiadi AF, Omilusik K, David MD, Seipp RP, Hartikainen J, Gopaul R, Choi KB, Jefferies WA. Epigenetic enhancement of antigen processing and presentation promotes immune recognition of tumors. Cancer Res. 2008;68:9601–9607. PubMed

Khan AN, Gregorie CJ, Tomasi TB. Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother. 2008;57:647–654. PubMed PMC

Simova J, Pollakova V, Indrova M, Mikyskova R, Bieblova J, Stepanek I, Bubenik J, Reinis M. Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status. British Journal of Cancer. 2011;105:1533–1541. PubMed PMC

Smahel M, Síma P, Ludvíková V, Marinov I, Pokorná D, Vonka V. Immunisation with modified HPV16 E7 genes against mouse oncogenic TC-1 cell sublines with downregulated expression of MHC class I molecules. Vaccine. 2003;21:1125–1136. PubMed

Martini M, Testi MG, Pasetto M, Picchio MC, Innamorati G, Mazzocco M, Ugel S, Cingarlini S, Bronte V, Zanovello P, Krampera M, Mosna F, Cestari T, Riviera AP, Brutti N, Barbieri O, Matera L, Tridente G, Colombatti M, Sartoris S. IFN-gamma-mediated upmodulation of MHC class I expression activates tumor-specific immune response in a mouse model of prostate cancer. Vaccine. 2010;28:3548–3557. PubMed

Darnell JE., Jr Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–1421. PubMed

Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immuno. 2006;6:836–848. PubMed

Serrano A, Castro-Vega I, Redondo M. Role of gene methylation in antitumor immune response: implication for tumor progression. Cancers (Basel) 2011;3:1672–1690. PubMed PMC

Xue ZT, Sjögren HO, Salford LG, Widegren B. An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-dioxygenase 1 (IDO1) by combined treatment with zebularine and IFN-γ: Potential therapeutic use in autoimmune diseases. Molecular Immunology. 2012;51:101–111. PubMed

Niehrs C. Active DNA demethylation and DNA repair. Differentiation. 2009;77:1–11. PubMed

Vaissière T, Sawan C, Herceg Z. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat Res. 2008;659:40–48. PubMed

Creusot F, Acs G, Christman JK. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2′-deoxycytidine. J Biol Chem. 1982;257:2041–2048. PubMed

Thillainadesan G, Chitilian JM, Isovic M, Ablack JN, Mymryk JS, Tini M, Torchia J. TGF-β-dependent active demethylation and expression of the p15ink4b tumor suppressor are impaired by the ZNF217/CoREST complex. Mol Cell. 2012;46:636–649. PubMed

Seligson DB, Horvath S, McBrian MA, Mah V, Yu H, Tze S, Wang Q, Chia D, Goodglick L, Kurdistani SK. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol. 2009;174:1619–1628. PubMed PMC

Lin KY, Guarnieri FG, Staveley-O'Carroll KF, Levitsky HI, August JT, Pardoll DM, Wu TC. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res. 1996;56:21–26. PubMed

Smahel M, Sobotkova E, Bubenik J, Simova J, Zak R, Ludvikova V, Hajkova R, Kovarik J, Jelinek F, Povysil C, Marinov J, Vonka V. Metastatic MHC class I-negative mouse cells derived by transformation with human papillomavirus type 16. Br J Cancer. 2001;84:374–380. PubMed PMC

Bubeník J, Indrová M, Nemecková S, Malkovský M, Von Broen B, Pálek V, Anderlíková J. Solubilized tumour-associated antigens of methyl-cholanthrene-induced mouse sarcomas. Comparative studies by in vitro sensitization of lymph-node cells, macrophage electrophoretic mobility assay and transplantation tests. Int J Cancer. 1978;21:348–355. PubMed

Bubeník J, Koldovský P, Svoboda J, Klement V, Dvorák R. Induction of tumours in mice with three variants of rous sarcoma virus and studies on the immunobiology of these tumours. Folia Biol (Praha) 1967;13:29–39. PubMed

Foster BA, Gingrich JR, Kwon ED, Madias C, Greenberg NM. Characterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Cancer Res. 1997;57:3325–3330. PubMed

Torella D, Curcio A, Gasparri C, Galuppo V, De Serio D, Surace FC, Cavaliere AL, Leone A, Coppola C, Ellison GM, Indolfi C. Fludarabine prevents smooth muscle proliferation in vitro and neointimal hyperplasia in vivo through specific inhibiton of STAT-1 activation. Am J Physiol Heart Circ Physiol. 2007;292:H2935–2943. PubMed

Lukas J, Mazna P, Valenta T, Doubravska L, Pospichalova V, Vojtechova M, Fafilek B, Ivanek R, Plachy J, Novak J, Korinek V. Dazap2 modulates transcription driven by the Wnt effector TCF-4. Nucleic Acids Res. 2009;37:3007–3020. PubMed PMC

Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet. 2002;31:141–149. PubMed