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A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes
P F Robbins1, M El-Gamil, Y F Li
1Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
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.
Insights
Researchers identified a mutated beta-catenin gene product recognized by T cells in melanoma. This specific mutation, absent in normal tissues, generates a novel T cell epitope, offering insights into cancer immunology and potential therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Tumor antigens recognized by T cells are crucial for cancer immunity.
- While mouse models often show mutated gene products as antigens, human studies frequently identify non-mutated antigens.
- Beta-catenin is involved in cell adhesion and its mutations are common in cancers.
Purpose of the Study:
- To identify and characterize tumor antigens recognized by T cells in human melanoma.
- To investigate the role of gene mutations in generating tumor-specific T cell responses.
- To understand the mechanism by which a mutated beta-catenin peptide is presented by HLA-A24.
Main Methods:
- Isolation of a cDNA clone encoding beta-catenin from a melanoma patient's tumor.
- Sequencing and comparison of the isolated cDNA with the wild-type beta-catenin sequence.
- Identification of the T cell epitope using a melanoma-specific CTL line (TIL 1290).
- Peptide binding assays to confirm interaction with HLA-A24.
Main Results:
- A single base pair mutation in beta-catenin was identified in the patient's melanoma, altering a serine to phenylalanine at position 37.
- This mutation resulted in a unique peptide (amino acids 29-37) recognized by TIL 1290.
- The mutated peptide demonstrated binding to HLA-A24, suggesting it functions as a T cell epitope.
- The altered beta-catenin sequence was specific to the tumor and not found in normal tissues or other melanomas.
Conclusions:
- A mutated beta-catenin gene product can serve as a tumor-specific antigen recognized by T cells in human melanoma.
- The identified mutation generates a novel T cell epitope that binds to HLA-A24.
- Mutations in cell adhesion molecules like beta-catenin may contribute to the development of the malignant phenotype.
- This finding highlights the potential of targeting mutated antigens for cancer immunotherapy.