The mutational status of p53 can influence its recognition by human T-cells

Oncoimmunology
Katerina ShamalovCyrille J Cohen

Abstract

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 pres...Continue Reading

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Citations

Sep 11, 2019·Journal for Immunotherapy of Cancer·Shiran HoogiCyrille J Cohen
May 12, 2020·Molecular Carcinogenesis·Sara MerilCyrille J Cohen
May 18, 2020·International Journal of Molecular Sciences·Arjelle Decasa AgupitanYgal Haupt
May 24, 2019·Journal for Immunotherapy of Cancer·Hanan BesserYoram Louzoun
Apr 22, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Albert B DeLeo, Ettore Appella
May 18, 2019·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Sandra AssounGérard Zalcman
Oct 16, 2021·The Journal of Clinical Investigation·Aviyah PeriYardena Samuels

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Methods Mentioned

BETA
transgenic
transfection
flow cytometry
ELISA
PCR
FACS

Clinical Trials Mentioned

NCT00844506
NCT02275039
NCT02577588

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