Abstract
Histone deacetylase inhibitors (HDACi), including trichostatin A (TSA) and valproic acid, can alter the acetylation of histones in chromatin and enhance gene transcription. Previously we demonstrated that HDACi-treated tumor cells are capable of presenting antigen via the MHC class II pathway. In this study, we show that treatment with HDACi enhances the expression of molecules (TAP1, TAP2, LMP2, LMP7, Tapasin and MHC class I) involved in antigen processing and presentation via the MHC class I pathway in melanoma cells. HDACi treatment of B16F10 cells also enhanced cell surface expression of class I and costimulatory molecules CD40 and CD86. Enhanced transcription of these genes is associated with a significant increase in direct presentation of whole protein antigen and MHC class I-restricted peptides by TSA-treated B16F10 cells. Our data indicate that epigenetic modification can convert a tumor cell to an antigen presenting cell capable of activating IFN-γ secreting T cells via the class I pathway. These findings suggest that the abnormalities, observed in some tumors in the expression of MHC class I antigen processing and presentation molecules, may result from epigenetic repression.
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Abbreviations
- CTL:
-
Cytotoxic T lymphocyte
- HDACi:
-
Histone deacetylase inhibitors
- TSA:
-
Trichostatin A
- VA:
-
Valproic acid
- APC:
-
Antigen presenting cell
- ova:
-
Ovalbumin
References
Agrawal S, Reemtsma K, Bagiella E, Oluwole SF, Braunstein NS (2004) Role of TAP-1 and/or TAP-2 antigen presentation defects in tumorigenicity of mouse melanoma. Cell Immunol 228:130–137
Armeanu S, Bitzer M, Lauer UM, Venturelli S, Pathil A, Krusch M, Kaiser S, Jobst J, Smirnow I, Wagner A, Steinle A, Salih HR (2005) Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res 65:6321–6329
Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6:107–116
Bertholet S, Debrabant A, Afrin F, Caler E, Mendez S, Tabbara KS, Belkaid Y, Sacks DL (2005) Antigen requirements for efficient priming of CD8+ T cells by Leishmania major-infected dendritic cells. Infect Immun 73:6620–6628
Chang C-C, Ogino T, Mullins DW, Oliver JL, Yamshchikov GV, Bandoh N, Slingluff CL Jr, Ferrone S (2006) Defective human leukocyte antigen class I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells. J Biol Chem 281:18763–18773
Chou S-D, Khan ANH, Magner WJ, Tomasi TB (2005) Histone acetylation regulates the cell type specific CIITA promoter, MHC class II expression and antigen presentation in tumor cells. Int Immunol 17:1483–1494
Ducasse M, Brown MA (2006) Epigenetic aberrations and cancer. Mol Cancer. http://www.molecular-cancer.com/content/5/1/60
Evans M, Borysiewicz LK, Evans AS, Rowe M, Jones M, Uzi Gileadi U, Vincenzo Cerundolo V, Man S (2001) Antigen processing defects in cervical carcinomas limit the presentation of a CTL epitope from human papillomavirus 16 E6. J Immunol 167:5420–5428
Feenstra M, Rozemuller E, Duran K, Stuy I, van den Tweel J, Slootweg P, de Weger R, Tilanus M (1999) Mutation in the beta-2 m gene is not a frequent event in head and neck squamous cell carcinomas. Hum Immunol 8:697–706
Fonsatti E, Sigalotti L, Coral S, Colizzi F, Altomonte M, Maio M (2003) Methylation-regulated expression of HLA class I antigens in melanoma. Int J Cancer 105:430–431
Groettrup M, Soza A, Kuckelkorn U, Kloetzel PM (1996) Peptide antigen production by the proteasome: complexity provides efficiency. Immunol Today 17:429–435
Hicklin DJ, Marincola FM, Ferrone S (1999) HLA class I antigen downregulation in human cancers: T cell immunotherapy revives an old story. Mol Med Today 5:178–186
Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR (1994) T cell receptor antagonist peptides induce positive selection. Cell 76:17–27
Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080
Jimenez P, Canton J, Concha A, Cabrera T, Fernández M, Real LM, García A, Serrano A, Garrido F, Ruiz-Cabello F (2000) Microsatellite instability analysis in tumor with different mechanisms for total loss of HLA expression. Cancer Immunol Immunother 48:684–90
Johnstone RW, Licht JD (2003) Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4:13–18
Khan ANH, Magner WJ, Tomasi TB (2004) An epigenetically altered tumor cell vaccine. Cancer Immunol Immunother 53:748–754
Komatsu Y, Hayashi H (1998) Histone deacetylase inhibitors up-regulate the expression of cell surface MHC class I molecules in B16/BL6 cells. J Antibiot 51:89–91
Komatsu Y, Tomizaki K, Tsukamoto M, Kato T, Nishino N, Sato S, Yamori T, Tsuruo T, Furumai R, Yoshida M, Horinouchi S, Hayashi H (2001) Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Res 61:4459–4466
Lentschat A, Karahashi H, Michelsen KS, Thomas LS, Zhang W, Vogel SN, Arditi M (2005) Mastoparan, a G protein agonist peptide, differentially modulates TLR4- and TLR2-mediated signaling in human endothelial cells and murine macrophages. J Immunol 174:4252–4261
Li H, Ou X, Xiong J, Wang T (2006) HPV16E7 mediates HDAC chromatin repression and downregulation of MHC class I genes in HPV16 tumorigenic cells through interaction with an MHC class I promoter. Biochem Biophys Res Commun 349:1315–1321
Lin HY, Chen CS, Lin SP, Weng JR, Chen CS (2006) Targeting histone deacetylase in cancer therapy. Med Res Rev 26:397–413
Lou Y, Vitalis TZ, Basha G, Cai B, Chen SS, Choi KB, Jeffries AP, Elliott WM, Atkins D, Seliger B, Jefferies WA (2005) Restoration of the expression of transporters associated with antigen processing in lung carcinoma increases tumor-specific immune responses and survival. Cancer Res 65:7926–7933
Luo W, Wang X, Kageshita T, Wakasugi S, Karpf, Ferrone S (2006) Regulation of high molecular weight-melanoma associated antigen (HMW-MAA) gene expression by promoter DNA methylation in human melanoma cells. Oncogene 25:2873–2884
Maeda T, Towatari M, Kosugi H, Saito H (2000) Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 96:3847–3856
Magner WJ, Kazim AL, Stewart C, Romano MA, Catalano G, Grande C, Keiser N, Santaniello F, Tomasi TB (2000) Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol 165:7017–7024
Marks PA, Dokmanovic M (2005) Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin Investig Drugs 14:1497–1511
Mora-García ML, Duenas-González A, Hernández-Montes J, Cruz-Hernández ED, Pérez-Cárdenas E, Weiss-Steider B, Santiago-Osorio E, Ortíz-Navarrete VF, Rosales VH, Cantú D, Lizano-Soberón M, Rojo-Aguilar MP, Monroy-García A (2006) Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid. J Transl Med 4:55
Ogino T, Shigyo H, Ishii H, Katayama A, Miyokawa N, Harabuchi Y, Ferrone S (2006) HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 66:9281–9289
Osborne A, Zhang H, Yang WM, Seto E, Blanck G (2001) Histone deacetylase activity represses gamma interferon-inducible HLA-DR gene expression following the establishment of a DNase I-hypersensitive chromatin conformation. Mol Cell Biol 21:6495–6506
Ou J-N, Torrisani J, Unterberger A, Provençal N, Shikimi K, Karimi M, Ekström TJ, Szyf M (2007) Histone deacetylase inhibitor trichostatin A induces global and gene-specific DNA demethylation in human cancer cell lines. Biochem Pharmacol 73:1297–1307
Raffaghello L, Prigione I, Bocca P, Morandi, Camoriano M, Gambini C, Wang X, Ferrone S, Pistoia V (2005) Multiple defects of the antigen-processing machinery components in human neuroblastoma: immunotherapeutic implications. Oncogene 24:4634–4644
Romero JM, Jimenez P, Cabrera T, Cózar JM, Pedrinaci S, Tallada M, Garrido F, Ruiz-Cabello F (2005) Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer. Int J Cancer 113:605–610
Schoenberger SP, Jonges LE, Mooijaart RJ, Hartgers F, Toes RE, Kast WM, Melief CJ, Offringa R (1998) Efficient direct priming of tumor specific cytotxic T lymphocyte in vivo by an engineered APC. Cancer Res 58:3094–3100
Schoenhals GJ, Krishna RM, Grandea AG 3rd, Spies T, Peterson PA, Yang Y, Früh K (1999) Retention of empty MHC class I molecules by Tapasin is essential to reconstitute antigen presentation in invertebrate cells. EMBO J 18:743–753
Seliger B, Harders C, Lohmann S, Momberg F, Urlinger S, Tampe R, Huber C (1998) Down-regulation of the MHC class I antigen-processing machinery after oncogenic transformation of murine fibroblasts. Eur J Immunol 28:122–133
Seliger B, Maeurer MJ, Ferrone S (2000) Antigen-processing machinery breakdown and tumor growth. Immunol Today 21:455–464
Seliger B, Wollscheid U, Momburg F, Blankenstein T, Huber C (2000) Coordinate downregulation of multiple MHC class I antigen processing genes in chemical-induced murine tumor cell lines of distinct origin. Tissue Antigens 56:327–336
Seliger B, Wollscheid U, Momburg F, Blankenstein T, Huber C (2001) Characterization of the major histocompatibility complex class I deficiencies in B16 melanoma cells. Cancer Res 61:1095–1099
Serrano A, Tanzarella S, Lionello I, Mendez R, Traversari C, Ruiz-Cabello F, Garrido F (2001) Expression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2′-deoxycytidine treatment. Int J Cancer 94:243–251
Tomasi TB, Magner WJ, Khan ANH (2006) Epigenetic regulation of immune escape genes in cancer. Cancer Immunol Immunother 55:1159–1184
Zhao B, Hou S, Ricciardi RP (2003) Chromatin repression by COUP-TFII and HDAC dominates activation by NF-kappaB in regulating major histocompatibility complex class I transcription in adenovirus tumorigenic cells. Virology 306:68–76
Zika E, Greer SF, Zhu X-S, Ting JP (2003) Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation. Mol Cell Biol 23:3091–3102
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Supported by a National Institutes of Health grant HD 17013 and utilized core facilities of Roswell Park Cancer Institute’s NCI Cancer Center Support Grant CA16056.
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Khan, A.N.H., Gregorie, C.J. & Tomasi, T.B. Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother 57, 647–654 (2008). https://doi.org/10.1007/s00262-007-0402-4
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DOI: https://doi.org/10.1007/s00262-007-0402-4