Revelation of a cryptic major histocompatibility complex class II-restricted tumor epitope in a novel RNA-processing enzyme.
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.
D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015723:Gene Library; D015809:HLA-DR7 Antigen / Q000276:immunology*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000276:immunology*; D008969:Molecular Sequence Data; D017354:Point Mutation; D011062:Polynucleotide Adenylyltransferase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015809:HLA-DR7 Antigen; D012334:RNA, Neoplasm; D011062:Polynucleotide Adenylyltransferase