Identification of immunodominant regions among promiscuous HLA-DR-restricted CD4+ T-cell epitopes on the tumor antigen MAGE-3.
The molecular characterization of the CD4(+) T-cell epitope repertoire on human tumor antigens would contribute to both clinical investigation and cancer immunotherapy. In particular, the identification of promiscuous epitopes would be beneficial to a large number of patients with neoplastic diseases regardless of their HLA-DR type. MAGE-3 is a tumor-specific antigen widely expressed in solid and hematologic malignancies; therefore, is an excellent candidate antigen. We used a major histocompatability complex (MHC) class II epitope prediction algorithm, the TEPITOPE software, to predict 11 sequence segments of MAGE-3 that could form promiscuous CD4(+) T-cell epitopes. In binding assays, the synthetic peptides corresponding to the 11 predicted sequences bound at least 3 different HLA-DR alleles. Nine of the 11 peptides induced proliferation of CD4(+) T cells from both healthy subjects and melanoma patients. Four immunodominant regions (residues 111-125, 146-160, 191-205, and 281-295), containing naturally processed epitopes, were recognized by most of the donors, in association with 3 to 4 different HLA-DR alleles, thus covering up to 94% of the alleles expressed in whites. On the contrary, the other promiscuous regions (residues 161-175 and 171-185) contained epitopes not naturally processed in vitro. The immunodominant epitopes identified will be useful in the design of peptide-based cancer vaccines and in the study of the functional state of tumor-specific CD4(+) T cells in patients bearing tumors expressing MAGE-3.
Consogno
Giuseppe
G
Laboratory of Tumor Immunology, Cancer Immunotherapy and Gene Therapy Program, Functional Proteomics Centre HRS-IFOM, Università Vita-Salute San Raffaele, and MOLMED, SpA, DIBIT, Scientific Institute H. San Raffaele, Milan, Italy.
Manici
Simona
S
Facchinetti
Valeria
V
Bachi
Angela
A
Hammer
Juergen
J
Conti-Fine
Bianca M
BM
Rugarli
Claudio
C
Traversari
Catia
C
Protti
Maria Pia
MP
D000465:Algorithms; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes; D008545:Melanoma / Q000276:immunology / Q000473:pathology; D018448:Models, Immunological; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments