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| Home > Publications database > Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment. |
| Home > Publications database > Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment. |
| Journal Article | DKFZ-2023-00015 |
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2022
Frontiers Media
Lausanne
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Please use a persistent id in citations: doi:10.3389/fimmu.2022.1063313
Abstract: 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.
Keyword(s): Humans (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Thioredoxins: metabolism (MeSH) ; Tumor Microenvironment (MeSH) ; Antioxidants: metabolism (MeSH) ; T-Lymphocytes (MeSH) ; Neoplasms (MeSH) ; Oxidation-Reduction (MeSH) ; Oxidative Stress (MeSH) ; CAR T cells ; ROS ; cancer immunotherapy ; redox regulation ; thioredoxin-1 ; tumor microenvironment ; Thioredoxins ; Antioxidants
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