Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2'-deoxycytidine in cutaneous melanoma: immunotherapeutic implications.

Abstract

PURPOSE:

To investigate the potential of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) to improve the effectiveness of immunotherapeutic approaches against melanocyte differentiation antigens.

EXPERIMENTAL DESIGN:

The effect of 5-aza-CdR on the constitutive expression of gp100 was investigated in 11 human melanoma cell lines by real-time reverse transcription-PCR and indirect immunofluorescence (IIF) analyses. 5-aza-CdR-mediated changes in the levels of expression of human leukocyte antigen (HLA) class I antigens and HLA-A2 allospecificity, intercellular adhesion molecule-1 (ICAM-1), and leukocyte-function-associated antigen-3 were investigated by IIF analysis on melanoma cells under study. The recognition of gp100-positive Mel 275 melanoma cells, treated or not with 5-aza-CdR, by HLA-A2-restricted gp100((209-217))-specific CTL was investigated by (51)Cr-release assays, IFN-gamma release and IFN-gamma ELISPOT assays.

RESULTS:

The constitutive expression of gp100 was not affected by 5-aza-CdR on all melanoma cells investigated. Compared with untreated cells, the exposure of Mel 275 melanoma cells to 5-aza-CdR significantly (P < 0.05) up-regulated their expression of HLA class I antigens and of ICAM-1. These phenotypic changes significantly (P < 0.05) increased the lysis of 5-aza-CdR-treated Mel 275 melanoma cells by gp100-specific CTL and increased their IFN-gamma release. 5-aza-CdR treatment of Mel 275 cells also induced a higher number of gp100-specific CTL to secrete IFN-gamma.

CONCLUSIONS:

Treatment with 5-aza-CdR improves the recognition of melanoma cells by gp100-specific CTL through the up-regulation of HLA class I antigens expression; ICAM-1 also contributes to this phenomenon. These findings highlight a broader range of therapeutic implications of 5-aza-CdR when used in association with active or adoptive immunotherapeutic approaches against a variety of melanoma-associated antigens.

• Authors: Ester Fonsatti, Hugues J M Nicolay, Luca Sigalotti, Luana Calabrò, Laura Pezzani, Francesca Colizzi, Maresa Altomonte, Massimo Guidoboni, Francesco M Marincola, Michele Maio
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 11 Pg. 3333-8 (Jun 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17545540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class I
• Membrane Glycoproteins
• PMEL protein, human
• gp100 Melanoma Antigen
• Decitabine
• Interferon-gamma
• Azacitidine

Topics

• Azacitidine (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Decitabine
• Fluorescent Antibody Technique, Indirect
• Gene Expression Regulation, Neoplastic
• Histocompatibility Antigens Class I (biosynthesis)
• Humans
• Immunotherapy (methods)
• Interferon-gamma (metabolism)
• Melanoma (drug therapy, immunology)
• Membrane Glycoproteins (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Skin Neoplasms (drug therapy, immunology)
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Up-Regulation
• gp100 Melanoma Antigen