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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Identification of p53 peptides recognized by CD8(+) T lymphocytes from patients with bladder cancer
1INSERM U445, Laboratoire Associé No9 du Comité de Paris de la Ligue contre le Cancer, Institut Cochin de Génétique Moléculaire, Université René Descartes, Paris, France. ferries@cochin.inserm.fr
Abstract:
In many types of cancer, p53 frequently accumulates in tumor cells and anti-p53 antibodies can be detected. However, only four CD8(+) T-cell epitopes from p53 have been identified in humans so far. To further analyze the development of a T-cell response against p53, peptides having binding motifs specific for HLA-A1, -A2, -A3, -A24, -B7, -B35, -B44, and -B51 molecules have been defined. The HLA-binding capacity of those peptides was tested, and the stability of formed complexes was defined. Thirteen peptides that bound to HLA-A24 and -B44 molecules are presented. The positive peptides were then used to detect the anti-p53 response of CD8(+) T lymphocytes from patients with bladder cancer. Six peptides, presented by HLA-A2, -B51, or -A24, were able to stimulate T cells from two patients (among 16) with tumor cells that strongly accumulated p53. On the contrary, p53 peptides systematically failed to stimulate T cells from healthy donors or patients with low or undetectable levels of p53 in their tumor cells. These results have led to the identification of four new potential T CD8(+) epitopes from p53: 194-203 associating with HLA-B51 and 204-212, 211-218, and 235-243 associating with HLA-A24.
Insights
Researchers identified new CD8(+) T-cell epitopes from the p53 tumor suppressor protein. These epitopes are crucial for detecting T-cell responses in cancer patients, particularly those with bladder cancer and high p53 accumulation.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- p53 protein accumulates in many cancer cells, triggering an antibody response.
- Identifying CD8(+) T-cell epitopes is crucial for understanding anti-tumor immunity.
- Previous research identified only four human CD8(+) T-cell epitopes from p53.
Purpose of the Study:
- To identify novel CD8(+) T-cell epitopes from p53.
- To analyze T-cell responses against p53 in cancer patients.
- To investigate the role of p53 T-cell epitopes in bladder cancer.
Main Methods:
- Designed peptides with binding motifs for specific HLA molecules (e.g., HLA-A24, -B44).
- Tested peptide binding capacity and complex stability with HLA molecules.
- Stimulated CD8(+) T lymphocytes from bladder cancer patients using identified p53 peptides.
Main Results:
- Thirteen peptides showed binding to HLA-A24 and -B44 molecules.
- Six peptides stimulated T cells in two out of 16 bladder cancer patients with high p53 levels.
- No T-cell stimulation was observed in healthy donors or patients with low p53 levels.
- Identified four new potential CD8(+) T-cell epitopes: p53(194-203)/HLA-B51, p53(204-212)/HLA-A24, p53(211-218)/HLA-A24, and p53(235-243)/HLA-A24.
Conclusions:
- Successfully identified four novel p53-derived CD8(+) T-cell epitopes.
- These epitopes can stimulate T cells in cancer patients with high p53 accumulation.
- The findings contribute to developing p53-targeted immunotherapies.
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