Home > Publications database > Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment. > print

001     186563
005     20240917155143.0
024 7 _ |a 10.3389/fimmu.2022.1063313
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041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Balta, Emre
|b 0
245 _ _ |a Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment.
260 _ _ |a Lausanne
|c 2022
|b Frontiers Media
336 7 _ |a article
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520 _ _ |a 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.
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650 _ 7 |a CAR T cells
|2 Other
650 _ 7 |a ROS
|2 Other
650 _ 7 |a cancer immunotherapy
|2 Other
650 _ 7 |a redox regulation
|2 Other
650 _ 7 |a thioredoxin-1
|2 Other
650 _ 7 |a tumor microenvironment
|2 Other
650 _ 7 |a Thioredoxins
|0 52500-60-4
|2 NLM Chemicals
650 _ 7 |a Antioxidants
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Immunotherapy, Adoptive: methods
|2 MeSH
650 _ 2 |a Thioredoxins: metabolism
|2 MeSH
650 _ 2 |a Tumor Microenvironment
|2 MeSH
650 _ 2 |a Antioxidants: metabolism
|2 MeSH
650 _ 2 |a T-Lymphocytes
|2 MeSH
650 _ 2 |a Neoplasms
|2 MeSH
650 _ 2 |a Oxidation-Reduction
|2 MeSH
650 _ 2 |a Oxidative Stress
|2 MeSH
700 1 _ |a Janzen, Nina
|b 1
700 1 _ |a Kirchgessner, Henning
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700 1 _ |a Toufaki, Vasiliki
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700 1 _ |a Orlik, Christian
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700 1 _ |a Liang, Jie
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700 1 _ |a Lairikyengbam, Divya
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700 1 _ |a Abken, Hinrich
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700 1 _ |a Niesler, Beate
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700 1 _ |a Müller-Decker, Karin
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700 1 _ |a Ruppert, Thomas
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700 1 _ |a Samstag, Yvonne
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773 _ _ |a 10.3389/fimmu.2022.1063313
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