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.
Coral
Sandra
S
Department of Medical Oncology, Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Sigalotti
Luca
L
Colizzi
Francesca
F
Spessotto
Alberto
A
Nardi
Gianpaolo
G
Cortini
Enzo
E
Pezzani
Laura
L
Fratta
Elisabetta
E
Fonsatti
Ester
E
Di Giacomo
Anna Maria
AM
Nicotra
Maria Rita
MR
Natali
Pier Giorgio
PG
Altomonte
Maresa
M
Maio
Michele
M
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015788:HLA-A1 Antigen / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured; D014611:Vaccination; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; C104948:CTAG1B protein, human; D015788:HLA-A1 Antigen; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; C072011:MAGEA1 protein, human; C072013:MAGEA3 protein, human; D058950:Melanoma-Specific Antigens; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000077209:Decitabine; D001374:Azacitidine