Abstract
Emerging in vitro evidence points to an immunomodulatory activity of DNA hypomethylating drugs in human malignancies. We investigated the potential of 5-aza-2'-deoxycytidine (5-AZA-CdR) to modulate the expression of cancer testis antigens (CTA) and of HLA class I antigens by melanoma xenografts, and the resulting modifications in immunogenicity of neoplastic cells. Three primary cultures of melanoma cells, selected for immune phenotype and growth rate, were grafted into BALB/c nu/nu mice that were injected intraperitoneally with different dose- and time-schedules of 5-AZA-CdR. Molecular analyses demonstrated a de novo long-lasting expression of the CTA MAGE-1, -2, -3, -4, -10, GAGE 1-6, NY-ESO-1, and the upregulation of MAGE-1, MAGE-3, and NY-ESO-1 levels in melanoma xenografts from 5-AZA-CdR-treated mice. Serological and biochemical analyses identified a de novo expression of NY-ESO-1 protein and a concomitant and persistent upregulation of HLA class I antigens and of HLA-A1 and -A2 alleles. Immunization of BALB/c mice with 5-AZA-CdR-treated melanoma cells generated high titer circulating anti-NY-ESO-1 antibodies. Altogether, the data obtained identify an immunomodulatory activity of 5-AZA-CdR in vivo and strongly suggest for its clinical use to design novel strategies of CTA-based chemo-immunotherapy for melanoma patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibody Formation / immunology
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / metabolism
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Antimetabolites, Antineoplastic / administration & dosage
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Antimetabolites, Antineoplastic / pharmacology
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Antimetabolites, Antineoplastic / therapeutic use
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Azacitidine / administration & dosage
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Azacitidine / therapeutic use
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DNA Methylation / drug effects*
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Decitabine
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Female
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Gene Expression / drug effects
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Gene Expression / genetics
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HLA-A1 Antigen / metabolism
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HLA-A2 Antigen / metabolism
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Histocompatibility Antigens Class I / metabolism
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Humans
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Immunotherapy / methods*
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Melanoma, Experimental / genetics
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Melanoma, Experimental / pathology
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Melanoma, Experimental / therapy*
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Melanoma-Specific Antigens
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Proteins / genetics
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Tumor Cells, Cultured
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Vaccination
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Xenograft Model Antitumor Assays*
Substances
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Antigens, Neoplasm
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Antimetabolites, Antineoplastic
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CTAG1B protein, human
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HLA-A1 Antigen
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HLA-A2 Antigen
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Histocompatibility Antigens Class I
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MAGEA1 protein, human
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MAGEA3 protein, human
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Melanoma-Specific Antigens
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Membrane Proteins
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Neoplasm Proteins
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Decitabine
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Azacitidine