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

• Verfasst von: Legscha, Kevin Jan [VerfasserIn]
• Verfasst von: Ferreira, Edite Antunes [VerfasserIn]
• Verfasst von: Chamoun, Antonios [VerfasserIn]
• Verfasst von: Lang, Alexander [VerfasserIn]
• Verfasst von: Awwad, Mohamed [VerfasserIn]
• Verfasst von: Ton, Gigi Nu Hoang Quy [VerfasserIn]
• Verfasst von: Galetzka, Danuta [VerfasserIn]
• Verfasst von: Guezguez, Borhane [VerfasserIn]
• Verfasst von: Hundemer, Michael [VerfasserIn]
• Verfasst von: Bourdon, Jean-Christophe [VerfasserIn]
• Verfasst von: Munder, Markus [VerfasserIn]
• Verfasst von: Theobald, Matthias [VerfasserIn]
• Verfasst von: Echchannaoui, Hakim [VerfasserIn]
• Titel: Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity
• Verf.angabe: Kevin Jan Legscha, Edite Antunes Ferreira, Antonios Chamoun, Alexander Lang, Mohamed Hemaid Sayed Awwad, Gigi Nu Hoang Quy Ton, Danuta Galetzka, Borhane Guezguez, Michael Hundemer, Jean-Christophe Bourdon, Markus Munder, Matthias Theobald, Hakim Echchannaoui
• E-Jahr: 2021
• Jahr: 10 June 2021
• Umfang: 15 S.
• Fussnoten: Gesehen am 04.11.2021
• Titel Quelle: Enthalten in: Journal for ImmunoTherapy of Cancer
• Ort Quelle: London : BioMed Central, 2013
• Jahr Quelle: 2021
• Band/Heft Quelle: 9(2021), 6, Artikel-ID e001846, Seite 1-15
• ISSN Quelle: 2051-1426
• DOI: doi:10.1136/jitc-2020-001846
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: adoptive
• Sach-SW: antigen
• Sach-SW: cell engineering
• Sach-SW: costimulatory and inhibitory T-cell receptors
• Sach-SW: immunotherapy
• Sach-SW: receptors
• Sach-SW: T-lymphocytes
• K10plus-PPN: 1776176693

Abstract

Background 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. - Methods 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. - Results 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+ and CD160+ CD8+ T cell populations, and an increased number of less differentiated CD28+ 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. - Conclusion 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.