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A wild-type p53 cytotoxic T cell epitope is presented by mouse hepatocarcinoma cells
V Lacabanne1, M Viguier, J G Guillet
1INSERM U455, Institut Cochin de Génétique Moléculaire (ICGM)-Université René Descartes, Paris, France. lacabane@cochin.inserm.fr
Abstract:
The possibility to identify epitopes presented by tumor cells to cytotoxic T lymphocytes (CTL) has given rise to new fields in tumor immunology. The tumor suppressor gene product p53 is a good candidate antigen because it is involved in the tumorigenesis of many cancers. It accumulates in an inactivated form due to mutation or formation of heterodimers with an oncogene product. Epitopes from the mutant or wild-type p53 proteins are thought to be presented by tumor cells and to induce a tumor-specific CTL response. To identify such epitopes, mouse wild-type p53 peptides encompassing the H-2 Db anchoring motif were tested for their association with the Db molecule. Positive peptides were assayed for their ability to induce CTL in C57BL/6 mice. CTL specific for one wild-type p53 peptide, p232-240, were isolated and found to lyse hepatocarcinoma cell lines established from mice transgenic for simian virus 40 large T antigen which overexpress p53. These results show that the p232-240 epitope from wild-type p53 is naturally processed and presented in H-2b tumor cells.
Insights
Researchers identified a specific wild-type p53 peptide (p232-240) that is naturally processed and presented by tumor cells. This finding advances tumor immunology by revealing a target for cytotoxic T lymphocyte (CTL) responses against cancer.
Area of Science:
- Tumor immunology
- Molecular oncology
- T cell immunology
Background:
- Cytotoxic T lymphocytes (CTLs) recognize tumor antigens presented by tumor cells, driving anti-tumor immune responses.
- The p53 tumor suppressor protein is frequently altered in cancer and can accumulate in an inactivated form.
- Identifying tumor-specific epitopes is crucial for developing targeted immunotherapies.
Purpose of the Study:
- To identify naturally processed and presented wild-type p53 epitopes.
- To investigate the potential of these epitopes to elicit a tumor-specific CTL response.
- To validate the presentation of a specific p53 epitope in H-2b tumor cells.
Main Methods:
- Screening of mouse wild-type p53 peptides for binding to the H-2 Db MHC class I molecule.
- Assaying peptide-induced CTL responses in C57BL/6 mice.
- Isolation and characterization of antigen-specific CTLs.
- Assessment of CTL-mediated lysis of tumor cell lines.
Main Results:
- Several wild-type p53 peptides were found to associate with the H-2 Db molecule.
- A specific peptide, p232-240, induced a CTL response in mice.
- CTLs specific for the p232-240 epitope were isolated.
- These CTLs effectively lysed hepatocarcinoma cell lines overexpressing p53.
Conclusions:
- The p232-240 epitope derived from wild-type p53 is naturally processed and presented by H-2b tumor cells.
- This epitope represents a potential target for tumor-specific CTL-mediated immunotherapy.
- The findings contribute to understanding p53's role in anti-tumor immunity.