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

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 (Lead / Corresponding author)

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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.

Original languageEnglish
Article numbere001846
Number of pages15
JournalJournal for immunotherapy of cancer
Volume9
Issue number6
Early online date10 Jun 2021
DOIs
Publication statusPublished - 10 Jun 2021

Keywords

  • adoptive
  • antigen
  • cell engineering
  • costimulatory and inhibitory T-cell receptors
  • immunotherapy
  • receptors
  • T-lymphocytes

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