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Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes
M Theobald1, J Biggs, J Hernández
1Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
Abstract:
Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer. A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells. The combination of p53 deficient (p53-/-) and p53+/+ HLA-A2.1/Kb transgenic mice was used as a model to explore the possibility that A2.1-restricted cytotoxic T lymphocytes (CTL) are functionally tolerant of self peptides derived from the wild-type p53 tumor suppressor protein. A2.1-restricted CTL specific for a naturally processed p53 self-epitope spanning residues 187-197 were completely aborted in p53+/+ as opposed to p53-/- transgenic mice. In contrast, CTL specific for a second self-epitope spanning residues 261-269 of the murine p53 sequence were detected in both p53-/- and p53+/+ A2.1/Kb transgenic mice. However, the avidity of the CTL effectors obtained from p53+/+ mice was 10-fold lower than that obtained from p53-/- mice, again suggesting elimination of CTL with high avidity for the A2.1-peptide complex. The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.
Insights
T cell tolerance can hinder p53 immunotherapy. Researchers found that high-avidity T cells targeting wild-type p53 epitopes were eliminated in mice, suggesting a need to overcome this tolerance for effective cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The p53 protein is a tumor suppressor found in about 50% of human cancers, making it a promising target for cancer immunotherapy.
- T cell tolerance to wild-type p53 antigens, due to low expression in normal tissues, presents a significant challenge for developing p53-specific immunotherapies and vaccines.
Purpose of the Study:
- To investigate whether T cells are functionally tolerant of self-peptides derived from wild-type p53.
- To explore the implications of this tolerance for the development of p53-targeted cancer immunotherapies.
Main Methods:
- Utilized a mouse model combining p53-deficient (p53-/-) and wild-type (p53+/+) HLA-A2.1/Kb transgenic mice.
- Assessed the generation and avidity of cytotoxic T lymphocytes (CTLs) specific for two distinct p53 self-epitopes (residues 187-197 and 261-269).
Main Results:
- CTLs specific for the p53 epitope (187-197) were completely absent in p53+/+ mice, indicating functional tolerance.
- CTLs specific for the p53 epitope (261-269) were detected in both p53-/- and p53+/+ mice, but with 10-fold lower avidity in p53+/+ mice.
- These findings suggest the elimination of high-avidity CTLs specific for wild-type p53 epitopes.
Conclusions:
- Functional tolerance to wild-type p53 epitopes can occur, particularly affecting high-avidity T cells.
- Overcoming this T cell tolerance is likely essential for optimizing immunotherapies targeting p53 epitopes, especially in the context of HLA-A2.1 restriction.
- This research provides critical insights for designing more effective cancer immunotherapies aimed at the p53 tumor suppressor protein.