> Details

Legscha, Kevin Jan; Antunes Ferreira, Edite; Chamoun, Antonios; Lang, Alexander; Awwad, Mohamed Hemaid Sayed; Ton, Gigi Nu Hoang Quy; Galetzka, Danuta; Guezguez, Borhane; Hundemer, Michael; Bourdon, Jean-Christophe; Munder, Markus; Theobald, Matthias; Echchannaoui, Hakim

Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity

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  • Media type: E-Article
  • Title: Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity
  • Contributor: Legscha, Kevin Jan; Antunes Ferreira, Edite; Chamoun, Antonios; Lang, Alexander; Awwad, Mohamed Hemaid Sayed; Ton, Gigi Nu Hoang Quy; Galetzka, Danuta; Guezguez, Borhane; Hundemer, Michael; Bourdon, Jean-Christophe; Munder, Markus; Theobald, Matthias; Echchannaoui, Hakim
  • imprint: BMJ, 2021
  • Published in: Journal for ImmunoTherapy of Cancer
  • Language: English
  • DOI: 10.1136/jitc-2020-001846
  • ISSN: 2051-1426
  • Keywords: Cancer Research ; Pharmacology ; Oncology ; Molecular Medicine ; Immunology ; Immunology and Allergy
  • Origination:
  • Footnote:
  • Description: <jats:sec><jats:title>Background</jats:title><jats:p>Tumor microenvironment-associated T cell senescence is a key limiting factor for durable effective cancer immunotherapy. A few studies have demonstrated the critical role of the tumor suppressor TP53-derived p53 isoforms in cellular senescence process of non-immune cells. However, their role in lymphocytes, in particular tumor-antigen (TA) specific T cells remain largely unexplored.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Human T cells from peripheral blood were retrovirally engineered to coexpress a TA-specific T cell receptor and the Δ133p53α-isoform, and characterized for their cellular phenotype, metabolic profile and effector functions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Phenotypic analysis of Δ133p53α-modified T cells revealed a marked reduction of the T-cell inhibitory molecules (ie, CD160 and TIGIT), a lower frequency of senescent-like CD57<jats:sup>+</jats:sup> and CD160<jats:sup>+</jats:sup> CD8<jats:sup>+</jats:sup> T cell populations, and an increased number of less differentiated CD28<jats:sup>+</jats:sup> T cells. Consistently, we demonstrated changes in the cellular metabolic program toward a quiescent T cell state. On a functional level, Δ133p53α-expressing T cells acquired a long-term proliferative capacity, showed superior cytokine secretion and enhanced tumor-specific killing in vitro and in mouse tumor model. Finally, we demonstrated the capacity of Δ133p53α to restore the antitumor response of senescent T cells isolated from multiple myeloma patients.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>This study uncovered a broad effect of Δ133p53α isoform in regulating T lymphocyte function. Enhancing fitness and effector functions of senescent T cells by modulation of p53 isoforms could be exploited for future translational research to improve cancer immunotherapy and immunosenescence-related diseases.</jats:p></jats:sec>
  • Access State: Open Access