Identification of immunodominant regions among promiscuous HLA-DR-restricted CD4+ T-cell epitopes on the tumor antigen MAGE-3.

Abstract

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.

• Authors: Giuseppe Consogno, Simona Manici, Valeria Facchinetti, Angela Bachi, Juergen Hammer, Bianca M Conti-Fine, Claudio Rugarli, Catia Traversari, Maria Pia Protti
• Journal: Blood (Blood) Vol. 101 Issue 3 Pg. 1038-44 (Feb 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12393675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Neoplasm
• Epitopes, T-Lymphocyte
• HLA-DR Antigens
• Histocompatibility Antigens Class II
• Immunodominant Epitopes
• MAGEA3 protein, human
• Neoplasm Proteins
• Peptide Fragments

Topics

• Algorithms
• Amino Acid Sequence
• Antigens, Neoplasm (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Epitopes, T-Lymphocyte
• HLA-DR Antigens (immunology)
• Histocompatibility Antigens Class II (immunology)
• Humans
• Immunodominant Epitopes
• Melanoma (immunology, pathology)
• Models, Immunological
• Molecular Sequence Data
• Neoplasm Proteins (immunology)
• Peptide Fragments (chemical synthesis, immunology)