Revelation of a cryptic major histocompatibility complex class II-restricted tumor epitope in a novel RNA-processing enzyme

• Published in: Cancer research (Chicago, Ill.) Ill.), 2002-10, Vol.62 (19), p.5505-5509
• Main Authors: TOPALIAN, Suzanne L, GONZALES, Monica I, WARD, Yvona, XIANG WANG, WANG, Rong-Fu
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Amino Acid Sequence; Antigens, Neoplasm - immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Gene Library; HLA-DR7 Antigen - immunology; Host-tumor relations. Immunology. Biological markers; Humans; Male; Medical sciences; Melanoma - enzymology; Melanoma - immunology; Molecular Sequence Data; Point Mutation; Polynucleotide Adenylyltransferase - genetics; Polynucleotide Adenylyltransferase - immunology; Polynucleotide Adenylyltransferase - metabolism; RNA, Neoplasm - metabolism; Subcellular Fractions - enzymology; Tumors
• ISSN: 0008-5472; 1538-7445

CD4+ T-cell responses against human tumor antigens are a potentially critical component of the antitumor immune response. Molecular methods have been devised for rapidly identifying MHC class II-restricted tumor antigens and elucidating the recognized epitopes. We describe here the identification of neo-poly(A) polymerase (neo-PAP), a novel RNA processing enzyme overexpressed in a variety of human cancers, by screening a melanoma-derived invariant chain fusion cDNA library with tumor-reactive CD4+ T lymphocytes. A cryptic nonmutated HLA-DRbeta1*0701-restricted neo-PAP epitope was processed through the endogenous MHC class II pathway. A unique point mutation effected a nonconservative substitution of a leucine for a proline residue at a structurally important site in neo-PAP that was remote from the recognized peptide, revealing a normally silent epitope for immune recognition. Genetic aberrations such as the described point mutation can have unexpected immunological consequences, in this case leading to immune recognition of a distant normal self epitope.