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

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.