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Published on: January 9, 2020
A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma
S Mandruzzato1, F Brasseur, G Andry
1Ludwig Institute for Cancer Research, Brussels Branch, and Unité de Génétique Cellulaire, Université Catholique de Louvain, B-1200 Brussels, Belgium.
Abstract:
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.
Insights
Researchers identified a novel tumor antigen on oral squamous cell carcinoma, encoded by a mutated CASP-8 gene. This discovery expands the known targets for T cell therapies beyond melanoma and kidney cancer.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Previously, tumor antigens recognized by T cells were primarily identified in melanoma and renal cell carcinoma.
- Autologous cytolytic T lymphocytes play a crucial role in anti-tumor immunity.
Purpose of the Study:
- To identify and characterize novel tumor antigens recognized by T cells in squamous cell carcinoma of the oral cavity.
- To investigate the genetic basis and functional implications of the identified tumor antigen.
Main Methods:
- Identification of tumor antigens using autologous cytolytic T lymphocytes.
- Genetic sequencing to identify mutations in antigen-encoding genes.
- Analysis of protein structure and function related to apoptosis induction.
Main Results:
- A novel tumor antigen was identified on human oral squamous cell carcinoma.
- The antigen is encoded by a mutated CASP-8 gene (also known as FLICE or MACH), with a modified stop codon and an added Alu repeat.
- The mutation results in an 88-amino acid protein extension, potentially reducing apoptosis-inducing activity.
- The antigenic peptide is a nonamer presented by HLA-B*3503, with the extended sequence contributing to the antigen.
Conclusions:
- This study identifies a new tumor antigen in oral cancer, expanding the repertoire of targets for T cell-based therapies.
- The mutated CASP-8 gene suggests a link between mutations generating tumor antigens and their role in tumor development or progression.
- The findings support the hypothesis that mutations in genes like CASP-8, CDK4, and beta-catenin can contribute to both tumor antigenicity and oncogenesis.
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