Treatment with 5-aza-2'-deoxycytidine induces expression of NY-ESO-1 and facilitates cytotoxic T lymphocyte-mediated tumor cell killing
Open accessAbstract
BACKGROUND: NY-ESO-1 belongs to the cancer/testis antigen (CTA) family and represents an attractive target for cancer immunotherapy. Its expression is induced in a variety of solid tumors via DNA demethylation of the promoter of CpG islands. However, NY-ESO-1 expression is usually very low or absent in some tumors such as breast cancer or multiple myeloma. Therefore, we established an optimized in vitro treatment protocol for up-regulation of NY-ESO-1 expression by tumor cells using the hypomethylating agent 5-aza-2'-deoxycytidine (DAC). METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated de novo induction of NY-ESO-1 in MCF7 breast cancer cells and significantly increased expression in U266 multiple myeloma cells. This effect was time- and dose-dependent with the highest expression of NY-ESO-1 mRNA achieved by the incubation of 10 μM DAC for 72 hours. NY-ESO-1 activation was also confirmed at the protein level as shown by Western blot, flow cytometry, and immunofluorescence staining. The detection and quantification of single NY-ESO-1 peptides presented at the tumor cell surface in the context of HLA-A*0201 molecules revealed an increase of 100% and 50% for MCF7 and U266 cells, respectively. Moreover, the enhanced expression of NY-ESO-1 derived peptides at the cell surface was accompanied by an increased specific lysis of MCF7 and U266 cells by HLA-A*0201/NY-ESO-1(157-165) peptide specific chimeric antigen receptor (CAR) CD8+ T cells. In addition, the killing activity of CAR T cells correlated with the secretion of higher IFN-gamma levels. CONCLUSIONS/SIGNIFICANCE: These results indicate that NY-ESO-1 directed immunotherapy with specific CAR T cells might benefit from concomitant DAC treatment.
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DNMT inhibitors are consistently linked to upregulation of tumor-associated antigens.
“upregulation of TAAs”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Klar et al., 2015
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Cites
A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening
Chen, Y., Scanlan, M. J., Şahin, U., Türeci, Ö., Gure, A. O., Tsang, S., Williamson, B., Stockert, E., Pfreundschuh, M. G., & Old, L. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.5.1914 · Cited by 1,247 · see citing works
The cancer/testis genes: review, standardization, and commentary.
Scanlan, M. J., Simpson, A. J. G., & Old, L. J. (2004) · PubMed · Cited by 669 · see citing works
Smet, C. D., Lurquin, C., Lethé, B., Martelange, V., & Boon, T. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.11.7327 · Cited by 598 · see citing works
NY‐ESO‐1: Review of an Immunogenic Tumor Antigen
Gnjatic, S., Nishikawa, H., Jungbluth, A. A., Gure, A. O., Ritter, G., Jäger, E., Knuth, A. K., Chen, Y., & Old, L. J. (2006) · Advances in cancer research · doi:10.1016/s0065-230x(06)95001-5 · Cited by 403 · see citing works
Monitoring CD8 T cell responses to NY-ESO-1: Correlation of humoral and cellular immune responses
Jäger, E., Nagata, Y., Gnjatic, S., Wada, H., Stockert, E., Karbach, J., Dunbar, P. R., Lee, S. Y., Jungbluth, A. A., Jäger, D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.9.4760 · Cited by 398 · see citing works
Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues
Jungbluth, A. A., Chen, Y., Stockert, E., BUSAM, K. J., Kolb, D., Iversen, K., Coplan, K. A., Williamson, B., Altorki, N. K., & Old, L. J. (2001) · International Journal of Cancer · doi:10.1002/ijc.1282 · Cited by 347 · see citing works
Human breast carcinoma cells in continuous culture: a review.
Engel, L. W., & Young, N. A. (1978) · PubMed · Cited by 345 · see citing works
Serrano, A., Tanzarella, S., Lionello, I., Méndez, R., Traversari, C., Ruiz‐Cabello, F., & Garrido, F. (2001) · International Journal of Cancer · doi:10.1002/ijc.1452 · Cited by 239 · see citing works
Schrump, D. S., Fischette, M. R., Nguyen, D. M., Zhao, M., Li, X., Kunst, T. F., Hancox, A., Hong, J. A., Chen, G. A., Pishchik, V., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0669 · Cited by 227 · see citing works
Sigalotti, L., Fratta, E., Coral, S., Tanzarella, S., Danielli, R., Colizzi, F., Fonsatti, E., Traversari, C., Altomonte, M., & Maio, M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1442 · Cited by 218 · see citing works
Nie, Y. (2001) · Carcinogenesis · doi:10.1093/carcin/22.10.1615 · Cited by 203 · see citing works
Wischnewski, F., Pantel, K., & Schwarzenbach, H. (2006) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-05-0229 · Cited by 185 · see citing works
Weiser, T. S., Guo, Z. S., Ohnmacht, G. A., Parkhurst, M. L., Tong-On, P., Marincola, F. M., Fischette, M. R., Yu, X., Chen, G. A., Hong, J. A., et al. (2001) · Journal of Immunotherapy · doi:10.1097/00002371-200103000-00010 · Cited by 162 · see citing works
Functional expression of chimeric receptor genes in human T cells
Eshhar, Z., Waks, T., Bendavid, A., & Schindler, D. G. (2001) · Journal of Immunological Methods · doi:10.1016/s0022-1759(00)00343-4 · Cited by 158 · see citing works
Identification of Novel Target Genes by an Epigenetic Reactivation Screen of Renal Cancer
de Cáceres, I. I., Dulaimi, E., Hoffman, A. M., Al‐Saleem, T., Uzzo, R. G., & Cairns, P. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3365 · Cited by 154 · see citing works
Heterogeneous expression of the SSX cancer/testis antigens in human melanoma lesions and cell lines.
dos Santos, N. R., Torensma, R., de Vries, T. J., et al. (2000) · PubMed · Cited by 151 · see citing works
Karpf, A. R., Lasek, A. W., Ririe, T. O., Hanks, A. N., Grossman, D., & Jones, D. A. (2004) · Molecular Pharmacology · doi:10.1124/mol.65.1.18 · Cited by 148 · see citing works
Coral, S., Sigalotti, L., Altomonte, M., Engelsberg, A., Colizzi, F., Cattarossi, I., Maraskovsky, E., Jäger, E., Seliger, B., & Maio, M. (2002) · PubMed · Cited by 143 · see citing works
Baxevanis, C. N., Perez, S. A., & Papamichail, M. (2008) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-008-0576-4 · Cited by 138 · see citing works
Enhancement of clonogenicity of human multiple myeloma by dendritic cells
Kukreja, A., Hutchinson, A., Dhodapkar, K. M., Mazumder, A., Vesole, D. H., Angitapalli, R., Jagannath, S., & Dhodapkar, M. V. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052136 · Cited by 134 · see citing works
Fonsatti, E., Nicolay, H. J. M., Sigalotti, L., Calabrò, L., Pezzani, L., Colizzi, F., Altomonte, M., Guidoboni, M., Marincola, F. M., & Maio, M. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-3091 · Cited by 131 · see citing works
Rational development of high-affinity T-cell receptor-like antibodies
Stewart-Jones, G., Wadle, A., Hombach, A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901425106 · Cited by 129 · see citing works
Self-citationCoral, S., Sigalotti, L., Gasparollo, A., Cattarossi, I., Visintin, A., Cattelan, A., Altomonte, M., & Maio, M. (1999) · Journal of Immunotherapy · doi:10.1097/00002371-199901000-00003 · Cited by 127 · see citing works
CT-X antigen expression in human breast cancer
Grigoriadis, A., Caballero, O. L., Hoek, K. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906840106 · Cited by 109 · see citing works
Cancer/testis tumour-associated antigens: immunohistochemical detection with monoclonal antibodies
Juretić, A., Spagnoli, G. C., Schultz‐Thater, E., & Šarčević, B. (2003) · The Lancet Oncology · doi:10.1016/s1470-2045(03)00982-3 · Cited by 105 · see citing works
Adair, S. J., & Hogan, K. T. (2008) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-008-0582-6 · Cited by 104 · see citing works
Mischo, A., Kubuschok, B., Ertan, K., Preuss, K., Romeike, B. F. M., Regitz, E., Schormann, C., de Bruijn, D. R. H., Wadle, A., Neumann, F., et al. (2005) · International Journal of Cancer · doi:10.1002/ijc.21352 · Cited by 101 · see citing works
Self-citationPurbhoo, M. A., Sutton, D. H., Brewer, J. E., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.12.7308 · Cited by 97 · see citing works
Natsume, A., Wakabayashi, T., Tsujimura, K., Shimato, S., Ito, M., Kuzushima, K., Kondo, Y., Sekido, Y., Kawatsura, H., Narita, Y., et al. (2008) · International Journal of Cancer · doi:10.1002/ijc.23407 · Cited by 93 · see citing works
Sigalotti, L., Coral, S., Altomonte, M., Natali, L., Gaudino, G., Cacciotti, P., Libener, R., Colizzi, F., Vianale, G., Martini, F., et al. (2002) · British Journal of Cancer · doi:10.1038/sj.bjc.6600174 · Cited by 88 · see citing works
Bao, L., DUNHAM, K. R., & Lucas, K. G. (2011) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-011-1037-z · Cited by 87 · see citing works
Held, G., Matsuo, M., Epel, M., et al. (2004) · European Journal of Immunology · doi:10.1002/eji.200425297 · Cited by 72 · see citing works
Theurillat, J.-P. P., Ingold, F., Frei, C., Zippelius, A., Varga, Z., Seifert, B., Chen, Y., Jäger, D., Knuth, A. K., & Moch, H. (2007) · International Journal of Cancer · doi:10.1002/ijc.22376 · Cited by 69 · see citing works
Altered MHC class I antigens in tumors
Algarra, I., Collado, A., & Garrido, F. (1997) · International Journal of Clinical & Laboratory Research · doi:10.1007/bf02912442 · Cited by 64 · see citing works
Schuberth, P., Jakka, G., Jensen, S. M., Wadle, A., Gautschi, F., Haley, D. P., Haile, S. R., Mischo, A., Held, G., Thiel, M., et al. (2012) · Gene Therapy · doi:10.1038/gt.2012.48 · Cited by 61 · see citing works
Self-citationMajor Histocompatibility Complex Expression on Human, Male Germ Cells: A Review
Fiszer, D., & Kurpisz, M. K. (1998) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.1998.tb00409.x · Cited by 59 · see citing works
Frumento, G., Franchello, S., Palmisano, G. L., et al. (2000) · Tissue Antigens · doi:10.1034/j.1399-0039.2000.560104.x · Cited by 51 · see citing works
HETEROGENEITY OF THE EXPRESSION OF CLASS I AND II HLA ANTIGENS IN HUMAN BREAST CARCINOMA
Pérez, M., Cabrera, T., López‐Nevot, M. Á., et al. (1986) · International Journal of Immunogenetics · doi:10.1111/j.1744-313x.1986.tb01108.x · Cited by 47 · see citing works
Expression of MAGE and BAGE genes in Japanese breast cancers
Fujie, T., Mori, M., Ueo, H., et al. (1997) · Annals of Oncology · doi:10.1023/a:1008255630202 · Cited by 47 · see citing works
Xin, H., Stephans, J. C., Duan, X., et al. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00014-4 · Cited by 20 · see citing works
Almunia, C., Bretaudeau, M., Held, G., Babon, A., Marchetti, C., Castelli, F. A., Ménèz, A., Maillère, B., & Gillet, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067645 · Cited by 15 · see citing works
Jakka, G., Schuberth, P., Thiel, M., et al. (2013) · PubMed · Cited by 10 · see citing works
Biological activity and binding of estradiol to SK-Mel 23 human melanoma cells
Sarti, M. S. M. V., Visconti, M. A., & Castrucci, A. M. D. L. (2004) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2004000600016 · Cited by 8 · see citing works
(2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905399106 · Cited by 7 · see citing works
Cancer Immunotherapy: Perspectives and Prospects
Perez, S. A., & Papamichail, M. (2008) · Springer eBooks · doi:10.1007/978-0-387-68969-2_19 · Cited by 3 · see citing works
Rational development of high-affinity T-cell receptor-like antibodies (vol 106, pg 5784, 2009)
Stewart-Jones, G., Wadle, A., Hombach, A. A., et al. (2009) · Proceedings of the National Academy of Sciences · Cited by 2 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- [29]Xin H, Stephans JC, Duan X, Harrowe G, Kim E, Grieshammer U, et al (2000) Identification of a novel aspartic-like protease differentially expressed in human breast cancer cell lines. Biochim Biophys Acta 1501: 125– 137. 10838186
- [34]Schirrmann TaP G (2007) Emerging Therapeutic Concepts III: Chimeric Immunoglobulin T Cell Receptors, T-Bodies, in Handbook of Therapeutic Antibodies. In: Dübel S, editor: Wiley-VCH Verlag GmbH.
Cited by
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Immunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212 · see citing works
- Authors
- Klar, A. S., Gopinadh, J., Kleber, S., Wadle, A., & Renner, C.
- Affiliations
- University Children's Hospital Zurich (CH)
- University Hospital Zurich (CH)
- University Hospital of Basel (CH)
- Corresponding author
- Klar, Agnes S.
- Renner, Christoph
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-10-08
- Volume
- 10
- Issue
- 10
- Pages
- e0139221
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4598131
- OpenAlex
- W2236008014
- Cited by
- 44
- References
- 46
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 3
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research Institute
- Kanton Zürich
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- NY-ESO-1, decitabine, DNA demethylation, cancer-testis antigens, cancer immunotherapy, chimeric antigen receptor T cells, HLA-A*0201, breast cancer, multiple myeloma, tumor cell killing, interferon-gamma, CpG island promoters
- MeSH terms
- Decitabine, Antigens, Neoplasm, Azacitidine, Breast Neoplasms, Female, Humans, Immunotherapy, Interferon-gamma, Membrane Proteins, Microscopy, Fluorescence, Multiple Myeloma, Peptides, Receptors, Antigen, T-Cell, T-Lymphocytes, Cytotoxic, HLA-A2 Antigen, Up-Regulation, Cell Line, Tumor, Real-Time Polymerase Chain Reaction, MCF-7 Cells
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