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

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 contribut...

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Main Authors: 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)
Format: Article (Journal)
Language:English
Published: 14 December 2022
In: Frontiers in immunology
Year: 2022, Volume: 13, Pages: 1-19
ISSN:1664-3224
DOI:10.3389/fimmu.2022.1063313
Online Access:Resolving-System, kostenfrei, Volltext: https://doi.org/10.3389/fimmu.2022.1063313
Verlag, kostenfrei, Volltext: https://www.frontiersin.org/articles/10.3389/fimmu.2022.1063313
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Author Notes:Emre Balta, Nina Janzen, Henning Kirchgessner, Vasiliki Toufaki, Christian Orlik, Jie Liang, Divya Lairikyengbam, Hinrich Abken, Beate Niesler, Karin Müller-Decker, Thomas Ruppert and Yvonne Samstag
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Summary: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.
Item Description:Gesehen am 23.01.2023
Physical Description:Online Resource
ISSN:1664-3224
DOI:10.3389/fimmu.2022.1063313

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