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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-03-0933.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 1038-1044
IMMUNOBIOLOGY
Identification of immunodominant regions among promiscuous
HLA-DR-restricted CD4+ T-cell epitopes on the tumor
antigen MAGE-3
Giuseppe Consogno,
Simona Manici,
Valeria Facchinetti,
Angela Bachi,
Juergen Hammer,
Bianca M. Conti-Fine,
Claudio Rugarli,
Catia Traversari, and
Maria Pia Protti
From the 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;
Department of Genomics and Information Sciences, Hoffmann-La Roche Inc,
Nutley, NJ; and Department of Medicine, Division of Hematology,
Oncology, and Transplantation, University of Minnesota, Minneapolis,
MN.
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.
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