The mutational status of p53 can influence its recognition by human T-cells
| Autor: | Cyrille J. Cohen, Miryam Horovitz-Fried, Shlomo N. Levy, Katerina Shamalov |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
p53
lcsh:Immunologic diseases. Allergy Immunology Antigen presentation CD1 Streptamer Biology lcsh:RC254-282 03 medical and health sciences Interleukin 21 0302 clinical medicine Immunology and Allergy Cytotoxic T cell tumor immunology Antigen-presenting cell t cells Original Research tcr ZAP70 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Molecular biology Oncology 030220 oncology & carcinogenesis Interleukin 12 Cancer research immunotherapy lcsh:RC581-607 030215 immunology |
| Zdroj: | OncoImmunology, Vol 6, Iss 4 (2017) |
| Popis: | p53 was reported to be an attractive immunotherapy target because it is mutated in approximately half of human cancers, resulting in its inactivation and often accumulation in tumor cells. Peptides derived from p53 are presented by class I MHC molecules and may act as tumor-associated epitopes which could be targeted by p53-specific T cells. Interestingly, it was recently shown that there is a lack of significant correlation between p53 expression levels in tumors and their recognition by p53-TCR transduced T cells. To better understand the influence of the mutational status of p53 on its presentation by the MHC system and on T cell antitumor reactivity, we generated several mutant p53 constructs and expressed them in HLA-A2+/p53− cells. Upon co-culture with p53-specific T cells, we measured the specific recognition of p53-expressing target cells by means of cytokine secretion, marker upregulation and cytotoxicity, and in parallel determined p53 expression levels by intracellular staining. We also examined the relevance of antigen presentation components on p53 recognition and the impact of mutant p53 expression on cell-cycle dynamics. Our results show that selected p53 mutations altering protein stability can modulate p53 presentation to T cells, leading to a differential immune reactivity inversely correlated with measured p53 protein levels. Thus, p53 may behave differently than other classical tumor antigens and its mutational status should therefore be taken into account when elaborating immunotherapy treatments of cancer patients targeting p53. |
| Databáze: | OpenAIRE |
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