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© The Rockefeller University Press, 0022-1007/1997/8/785/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 5, August 29, 1997 785-793

Article

A CASP-8 Mutation Recognized by Cytolytic T Lymphocytes on a Human Head and Neck Carcinoma

Susanna Mandruzzato*, Francis Brasseur*, Guy Andry{ddagger}, Thierry Boon*, and Pierre van der Bruggen*

From the * Ludwig Institute for Cancer Research, Brussels Branch, and Unité de Génétique Cellulaire, Université Catholique de Louvain, B-1200 Brussels, Belgium; and the {ddagger} Institut Jules Bordet, Service de Chirurgie, Université Libre de Bruxelles, B-1000 Brussels, Belgium

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 β-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.

Address correspondence to Pierre van der Bruggen, 74 avenue Hippocrate, B-1200 Bruxelles, Belgium. Phone: 32-2-764-74-31; FAX: 32-2-762-94-05; E-mail: vanderbruggen{at}licr.ucl.ac.be

S. Mandruzzato was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Italy and by a postdoctoral fellowship from the Training and Mobility of the Researchers program of the European Commission. This work was partially supported by the Belgian program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Office for Science, Technology and Culture, by CGER-Assurances (Belgium), and by BIOMED, a European Community program for Research and Technological Development.

1 Abbreviations used in this paper: FADD, Fas-associated death domain protein; FasL, Fas ligand; HS, human serum; MLTC, mixed lymphocyte– tumor cell culture; SCCHN, head and neck squamous cell carcinoma; TRADD, TNFR1-associated death domain protein.


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