Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: Immunotherapeutic implications

Authors

  • Sandra Coral,

    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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  • Luca Sigalotti,

    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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  • Francesca Colizzi,

    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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  • Alberto Spessotto,

    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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  • Gianpaolo Nardi,

    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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  • Enzo Cortini,

    1. Department of Oncology, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
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  • Laura Pezzani,

    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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  • Elisabetta Fratta,

    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
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  • Ester Fonsatti,

    1. Department of Oncology, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
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  • Anna Maria Di Giacomo,

    1. Department of Oncology, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
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  • Maria Rita Nicotra,

    1. Istituto di Biologia e Patologia Molecolare, Consiglio Nazionale delle Ricerche, Rome, Italy
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  • Pier Giorgio Natali,

    1. Laboratory of Immunology, Centro Ricerca Sperimentale, Istituto Regina Elena, Rome, Italy
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  • Maresa Altomonte,

    1. Department of Oncology, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
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  • Michele Maio

    Corresponding author
    1. Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
    2. Department of Oncology, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
    • Department of Oncology, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Strada delle Scotte 14, Siena 53100, Italy.
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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. J. Cell. Physiol. 207: 58–66, 2006. © 2005 Wiley-Liss, Inc.

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