Unbalanced expression of HLA-A and -B antigens: a specific feature of cutaneous melanoma and other non-hemopoietic malignancies reverted by IFN-gamma.
Conflicting evidences suggested that levels of HLA-A and -B antigens expressed on normal and neoplastic cells of given individuals are genetically predetermined, or, on the other hand, regulated by molecular mechanisms generating the down-regulated expression of HLA-B antigens frequently observed on melanoma cells. In our study, we quantitated, both at the protein and mRNA level, the amounts of HLA-A and -B antigens constitutively expressed on 23 primary cultures of metastatic melanomas and on autologous peripheral blood mononuclear cells (PBMC). Flow cytometric analyses identified a significantly (p < 0.01) lower expression of HLA-B antigens on melanoma cell cultures but not on autologous PBMC. Consistently, lower amounts of HLA-B antigens mRNA were detected by RNase protection assay exclusively in neoplastic cells. This unbalanced expression of HLA-A and -B antigens was readily reverted by interferon (IFN)-gamma but not by the DNA hypomethylating agent 5-aza-2'-deoxycytidine in 4 melanoma cell cultures investigated. Significantly (p < 0.05) lower levels of HLA-B antigens were also detected on cells from solid malignancies of different histotypes but not on neoplastic cells from hemopoietic neoplasms; levels of HLA-B antigens were rapidly up-regulated by IFN-gamma exclusively on non-hemopoietic transformed cells. Together, these data strongly argue against a genetic predetermination of the amounts of HLA-A and -B antigens expressed on normal and neoplastic cells of distinct melanoma patients and suggest that constitutively low levels of HLA-B antigens are a specific feature of non-hemopoietic transformed cells that is controlled by common regulatory mechanism(s) and that is possibly shared by non-hemopoietic normal cells.
Gasparollo
A
A
Advanced Immunotherapy Unit, Centro di Riferimento Oncologico, Istituto Nazionale di Ricovero e Cura a Carattere Scientifico, Via Pedemontana Occ.le, 12, Aviano, Italy 33081.
Coral
S
S
Ciullo
M
M
Prisco
A
A
Cattarossi
I
I
Sigalotti
L
L
Altomonte
M
M
Guardiola
J
J
Maio
M
M
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001483:Base Sequence; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D000077209:Decitabine; D015536:Down-Regulation; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000096:biosynthesis* / Q000235:genetics; D015235:HLA-B Antigens / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000077209:Decitabine; D007371:Interferon-gamma; D012260:Ribonucleases; D001374:Azacitidine