A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes.
Open accessAbstract
A number of antigens recognized by tumor-reactive T cells have recently been identified. The antigens identified in mouse model systems appear, with one exception, to represent the products of mutated genes. In contrast, most of the antigens recognized by human tumor-reactive T cells reported to date appear to represent the products of non-mutated genes. Here we report the isolation of a cDNA clone encoding beta-catenin, which was shown to be recognized by the tumor-infiltrating lymphocyte (TIL) 1290, a HLA-A24 restricted melanoma-specific CTL line from patient 888. The cDNA clone, which was isolated from the autologous melanoma cDNA library, differed by a single base pair from the published beta-catenin sequence, resulting in a change from a serine to a phenylalanine residue at position 37. Normal tissues from this patient did not express the altered sequence, nor did 12 allogeneic melanomas, indicating that this represented a unique mutation in this patient's melanoma. A peptide corresponding to the sequence between amino acids 29 and 37 of the mutant gene product was identified as the T cell epitope recognized by TIL 1290. The observation that HLA-A24 binding peptides contain an aromatic or hydrophobic residue at position 9 suggested that the change at position 37 may have generated a peptide (SYLDSGIHF) which was capable of binding to HLA-A24, and a competitive binding assay confirmed this hypothesis. The beta-catenin protein has been shown previously to be involved in cell adhesion mediated through the cadherin family of cell surface adhesion molecules. The high frequency of mutations found in members of cellular adhesion complexes in a variety of cancers suggests that these molecules may play a role in development of the malignant phenotype.
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Adoptive cell therapy involves genetically modifying T cells to express a chimeric antigen receptor or T cell receptor that recognizes specific antigens displayed on tumors, leading to clinical benefits.
“Adoptive cell therapy is an immunotherapy that involves genetically modifying T cells to express either a chimeric antigen receptor or T cell receptor (TCR) that can recognize specific antigens displayed on tumors, leading to clinical benefits.602,603”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [602]
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- Authors
- Robbins, P. F., El-Gamil, M., Li, Y. F., Kawakami, Y., Loftus, D., Appella, E., & Rosenberg, S. A.
- Affiliations
- National Institutes of Health (US)
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Venue
- The Journal of experimental medicine
- Publisher
- Rockefeller University Press
- Published
- 1996-03-01
- Volume
- 183
- Issue
- 3
- Pages
- 1185-1192
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2192326
- OpenAlex
- W2122507780
- Cited by
- 550
- References
- 28
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 4 · 2023: 10 · 2022: 10 · 2021: 9 · 2020: 19 · 2019: 21 · 2018: 15 · 2017: 15 · 2016: 17 · 2015: 12 · 2014: 12 · 2013: 10 · 2012: 12
- FWCI
- 15.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (MD 20892)
- National Cancer Institute (MD 20892, 20892)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- β-catenin, melanoma, tumor-specific antigens, tumor-infiltrating lymphocytes, cytotoxic T lymphocytes, HLA-A24, T cell epitopes, cDNA clones, peptide-MHC binding, adhesion molecules, cadherins, tumor immunology
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cell Line, Cloning, Molecular, Cytoskeletal Proteins, Humans, Kidney, Melanoma, Molecular Sequence Data, Organ Specificity, Peptides, Sequence Homology, Nucleic Acid, T-Lymphocytes, Transfection, Trans-Activators, Gene Library, Cadherins, Polymerase Chain Reaction, Lymphocytes, Tumor-Infiltrating, Mutagenesis, Point Mutation, Sequence Deletion, DNA Primers, DNA, Complementary, beta Catenin
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