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Balta, Emre [Author]; Janzen, Nina [Author]; Kirchgessner, Henning [Author]; Toufaki, Vasiliki [Author]; Orlik, Christian [Author]; Liang, Jie [Author]; Lairikyengbam, Divya [Author]; Abken, Hinrich [Author]; Niesler, Beate [Author]; Müller-Decker, Karin [Author]; Ruppert, Thomas [Author]; Samstag, Yvonne [Author]

Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment

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  • Media type: E-Article
  • Title: Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment
  • Contributor: Balta, Emre [Author]; Janzen, Nina [Author]; Kirchgessner, Henning [Author]; Toufaki, Vasiliki [Author]; Orlik, Christian [Author]; Liang, Jie [Author]; Lairikyengbam, Divya [Author]; Abken, Hinrich [Author]; Niesler, Beate [Author]; Müller-Decker, Karin [Author]; Ruppert, Thomas [Author]; Samstag, Yvonne [Author]
  • Published: 14 December 2022
  • Published in: Frontiers in immunology ; 13(2022), Artikel-ID 1063313, Seite 1-19
  • Language: English
  • DOI: 10.3389/fimmu.2022.1063313
  • Identifier:
  • Origination:
  • Footnote:
  • Description: Use of chimeric antigen receptor (CAR) T cells to treat B cell lymphoma and leukemia has been remarkably successful. Unfortunately, the therapeutic efficacy of CAR T cells against solid tumors is very limited, with immunosuppression by the pro-oxidative tumor microenvironment (TME) a major contributing factor. High levels of reactive oxygen species are well-tolerated by tumor cells due to their elevated expression of antioxidant proteins; however, this is not the case for T cells, which consequently become hypo-responsive. The aim of this study was to improve CAR T cell efficacy in solid tumors by empowering the antioxidant capacity of CAR T cells against the pro-oxidative TME. To this end, HER2-specific human CAR T cells stably expressing two antioxidant systems: thioredoxin-1 (TRX1), and glutaredoxin-1 (GRX1) were generated and characterized. Thereafter, antitumor functions of CAR T cells were evaluated under control or pro-oxidative conditions. To provide insights into the role of antioxidant systems, gene expression profiles as well as global protein oxidation were analyzed. Our results highlight that TRX1 is pivotal for T cell redox homeostasis. TRX1 expression allows CAR T cells to retain their cytolytic immune synapse formation, cytokine release, proliferation, and tumor cell-killing properties under pro-oxidative conditions. Evaluation of differentially expressed genes and the first comprehensive redoxosome analysis of T cells by mass spectrometry further clarified the underlying mechanisms. Taken together, enhancement of the key antioxidant TRX1 in human T cells opens possibilities to increase the efficacy of CAR T cell treatment against solid tumors.
  • Access State: Open Access