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p53: a potential target antigen for immunotherapy of cancer
R Offringa1, M P Vierboom, S H van der Burg
1Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands. R.Offringa@Immunohematology.MedFac.LeidenUniv.nl
Abstract:
Approximately 50% of all human malignancies exhibit mutation and aberrant expression of p53, making this protein an interesting candidate target for immunotherapy of cancer. Mutations in p53 are highly diverse. Therefore, targeting of determinants within the wild-type p53 sequence appears most practical. Despite the fact that p53 is ubiquitously expressed, adoptive immunotherapy of tumor-bearing mice with p53-specific cytotoxic T lymphocytes (CTL) results in eradication of p53-overexpressing tumors in the absence of immunopathological damage to normal tissues. These CTL also eliminate tumors that do not show greatly enhanced expression of p53, indicating that the sensitivity of these tumors for p53-specific CTL is determined by the efficiency by which p53-derived peptides are processed into class I MHC, rather than by the steady state levels of p53. Of note, although p53-specific CTL can readily be isolated from p53-/- mice, tolerance for this self antigen may prevent induction of similarly effective CTL in p53+/+ subjects. The T helper (Th) branch of the p53-specific immune response does not seem to be profoundly affected by tolerance. In addition, more and more evidence is obtained for the pivotal role of tumor-specific Th cells in the induction and effector phases of the antitumor response, also against tumors that lack class II MHC expression. The efficacy of Th cells, specific for a recently identified class II MHC-restricted p53 peptide, against p53-overexpressing tumors is currently being investigated. In addition, natural and induced Th responses are analyzed both in a murine tumor model and in a phase I clinical trial involving p53-specific vaccination of colon cancer patients.
Insights
Targeting the p53 protein offers a promising avenue for cancer immunotherapy. p53-specific T cell responses can effectively eliminate tumors, even with low p53 expression, highlighting potential therapeutic strategies.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- * About 50% of human cancers involve mutations or aberrant expression of the p53 protein.
- * Targeting wild-type p53 is a practical approach for cancer immunotherapy due to mutation diversity.
- * p53 is a ubiquitous protein, presenting challenges and opportunities for immune targeting.
Purpose of the Study:
- * To investigate the potential of p53-specific adoptive immunotherapy against various tumors.
- * To explore the role of cytotoxic T lymphocytes (CTL) and T helper (Th) cells in anti-p53 immune responses.
- * To assess the efficacy of p53-specific vaccination in preclinical models and clinical trials.
Main Methods:
- * Adoptive immunotherapy using p53-specific CTL in tumor-bearing mice.
- * Analysis of T cell responses (CTL and Th) in p53 knockout and wild-type mice.
- * Investigation of p53-derived peptides presented by MHC class I and class II.
- * p53-specific vaccination in a murine tumor model and a Phase I clinical trial for colon cancer.
Main Results:
- * Adoptive immunotherapy with p53-specific CTL eradicated p53-overexpressing tumors without damaging normal tissues.
- * CTL efficacy was linked to peptide processing and presentation via MHC class I, not solely p53 levels.
- * Tolerance to self p53 may limit CTL induction in wild-type subjects, but T helper responses remain viable.
- * Tumor-specific Th cells play a crucial role in antitumor responses, irrespective of MHC class II expression.
Conclusions:
- * p53-specific CTL immunotherapy is effective against tumors, with presentation efficiency being key.
- * T helper cell responses are crucial for antitumor immunity and are less affected by self-tolerance.
- * Further investigation into p53-specific Th cell efficacy and vaccination strategies is warranted for cancer treatment.