A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma.
Of the antigens recognized on human tumors by autologous cytolytic T lymphocytes, all those defined thus far have been identified on melanoma or renal cell carcinoma. We report here the identification of an antigen recognized by autologous cytolytic T lymphocytes on a human squamous cell carcinoma of the oral cavity. The antigen is encoded by a mutated form of the CASP-8 gene. This gene, also named FLICE or MACH, codes for protease caspase-8, which is required for induction of apoptosis through the Fas receptor and tumor necrosis factor receptor-1. The mutation, which was found in the tumor cells but not in the normal cells of the patient, modifies the stop codon and adds an Alu repeat to the coding region, thereby lengthening the protein by 88 amino acids. The ability of the altered protein to trigger apoptosis appears to be reduced relative to the normal caspase-8. The antigenic peptide is a nonamer presented by HLA-B*3503. The five last amino acids are encoded by the extension of the reading frame caused by the mutation. This, together with previous observations of CDK4 and beta-catenin mutations, suggests that a significant fraction of the point mutations generating a tumor antigen also play a role in the tumoral transformation or progression.
Mandruzzato
S
S
Ludwig Institute for Cancer Research, Brussels Branch, and Unité de Génétique Cellulaire, Université Catholique de Louvain, B-1200 Brussels, Belgium.
Brasseur
F
F
Andry
G
G
Boon
T
T
van der Bruggen
P
P
D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D017209:Apoptosis; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000276:immunology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000276:immunology*; D017354:Point Mutation; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D017421:Sequence Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D006680:HLA Antigens; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases