Relationship of p53 Overexpression on Cancers and Recognition by Anti-p53 T Cell Receptor-Transduced T Cells

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
Human gene therapy (Impact Factor: 3.76). 11/2008; 19(11):1219-32. DOI: 10.1089/hgt.2008.083
Source: PubMed


Tumor suppressor p53 is reported to be an attractive immunotherapy target because it is mutated in approximately half of human cancers, resulting in inactivation and often an accumulation of the protein in the tumor cells. Only low amounts of protein are detectable in normal tissues. The differential display of antigen in normal versus tumor tissues has been reported to create an opportunity to target p53 by immunotherapy. We sought to determine the relationship between p53 expression and its recognition by cognate T cells in human tumors including common epithelial malignancies. Inasmuch as nonsense or missense p53 mutations may disrupt processing and presentation, we studied tumors with either identified wild-type or mutated p53, based on our gene-sequencing studies or published data. T cells transduced with a high-affinity, p53(264-272)-reactive T cell receptor (TCR) derived from HLA-A2.1 transgenic mice recognized a wide panel of human tumor lines. There was no significant correlation between p53 expression in tumors and recognition by the anti-p53 TCR-transduced T cells. This conclusion was based on the study of 48 cell lines and is in contrast to several prior studies that used only a limited number of selected cell lines. A panel of normal cells was evaluated for recognition, and some of these populations were capable of stimulating anti-p53 T cells, albeit at low levels. These studies raise doubts concerning the suitability of targeting p53 in the immunotherapy of cancer patients.

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Available from: Azam V Nahvi, Jul 02, 2014
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    • "Wild-type p53 is a ubiquitously-expressed protein but the wild-type p53 protein expression in normal tissue is hardly detectable due to rapid degradation by a proteasome-dependent pathway, which eventually causes antigen presentation on HLA class I molecules [50], [51]. The specificity of CD8+ T cells to p53-accumulating tumors was recently investigated, leading to the observation that CD8+ T cells transduced with high affinity p53-specific T cell receptor gene could recognize not only p53-accumulating tumors but also tumors expressing wild-type p53, irrespective of the expression level of p53 protein, and normal cells such as peripheral blood stem cells and dendritic cells [52]. Because antigen presentation by professional APCs like DCs in non-inflammatory condition is known to induce tolerance, a constitutive presentation of wild-type p53 by DCs could be considered to induce tolerance of high-avidity p53-specific CD8+ T cells [53]. "
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