Epigenetic modulation of MAGE-A3 antigen expression in multiple myeloma following treatment with the demethylation agent 5-azacitidine and the histone deacetlyase inhibitor MGCD0103
| Autor: | H. Grant Prentice, Bart Barlogie, Antje Hoerring, Jackie Szymonifka, John D. Shaughnessy, Frits van Rhee, Amberly Moreno-Bost, Katie L. Stone, Tarun K. Garg, Susann Szmania |
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| Rok vydání: | 2011 |
| Předmět: |
Male
endocrine system Cancer Research medicine.drug_class medicine.medical_treatment Immunology Azacitidine Biology Epigenesis Genetic Antigens Neoplasm Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Secondary Prevention medicine Humans Immunology and Allergy Cytotoxic T cell neoplasms Genetics (clinical) Transplantation Histone deacetylase inhibitor Cell Biology Immunotherapy DNA Methylation Neoplasm Proteins Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors CTL Pyrimidines Oncology Tumor Escape Hypomethylating agent Benzamides Cancer research Cancer/testis antigens Female Multiple Myeloma T-Lymphocytes Cytotoxic medicine.drug |
| Zdroj: | Cytotherapy. 13:618-628 |
| ISSN: | 1465-3249 |
| DOI: | 10.3109/14653249.2010.529893 |
| Popis: | Immunotherapy targeting MAGE-A3 in multiple myeloma (MM) could eradicate highly aggressive and proliferative clonal cell populations responsible for relapse. However, expression of many cancer-testis antigens, including MAGE-A3, can be heterogeneous, leading to the potential for tumor escape despite MAGE-A3-induced immunity. We hypothesized that a combination of the hypomethylating agent 5-azacitidine (5AC) and the histone deacetylase inhibitor (HDACi) MGCD0103 (MGC) could induce MAGE-A3 expression in MAGE-A3-negative MM, resulting in recognition and killing of MM cells by MAGE-A3-specific cytotoxic T lymphocytes (CTL).Gene expression analyses of MAGE-A3 expression in primary MM patient samples at diagnosis and relapse were completed to identify populations that would benefit from MAGE-A3 immunotherapy. MM cell lines were treated with 5AC and MGC. Real-time polymerase chain reaction (PCR) and Western blotting were performed to assess MAGE-A3 RNA and protein levels, respectively. Chromium-release assays and interferon (IFN) secretion assays were employed to ascertain MAGE-A3 CTL specificity against treated targets.Gene expression analysis revealed that MAGE-A3 is expressed in MM patients at diagnosis (25%) and at relapse (49%). We observed de novo expression of MAGE-A3 RNA and protein in MAGE-A3-negative cell lines treated with 5AC. MGC treatment alone did not induce expression but sequential 5AC/MGC treatment led to enhanced expression and augmented recognition by MAGE-A3-specific CTL, as assessed by (51)Cr-release assays (P = 0.047) and enzyme-linked immunosorbent assay (ELISA) for IFN-γ secretion (P = 0.004).MAGE-A3 is an attractive target for immunotherapy of MM and epigenetic modulation by 5AC, and MGC can induce MAGE-A3 expression and facilitate killing by MAGE-A3-specific CTL. |
| Databáze: | OpenAIRE |
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