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Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells
Ying Yang, … , Kai Wang, Andreas Lundqvist
Ying Yang, … , Kai Wang, Andreas Lundqvist
Published July 16, 2020
Citation Information: J Clin Invest. 2020;130(10):5508-5522. https://doi.org/10.1172/JCI137585.
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Research Article Immunology Oncology Article has an altmetric score of 4

Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells

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Abstract

To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in which the abundance of ROS could dampen antitumor immune responses. In the present study, we demonstrated that IL-15–primed NK cells acquired resistance against oxidative stress through the thioredoxin system activated by mTOR. Mechanistically, the activation of thioredoxin showed dependence on localization of thioredoxin-interacting protein. We show that NK cells residing in the tumor core expressed higher thiol densities that could aid in protecting other lymphocytes against ROS within the TME. Furthermore, the prognostic value of IL15 and the NK cell gene signature in tumors may be influenced by tobacco smoking history in patients with non–small-cell lung cancer (NSCLC). Collectively, the levels of reducing antioxidants in NK cells may not only predict better tumor penetrance but potentially even the immune therapy response.

Authors

Ying Yang, Shi Yong Neo, Ziqing Chen, Weiyingqi Cui, Yi Chen, Min Guo, Yongfang Wang, Haiyan Xu, Annina Kurzay, Evren Alici, Lars Holmgren, Felix Haglund, Kai Wang, Andreas Lundqvist

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Figure 2

IL-15 upregulates thioredoxin activity in NK cells and reduces shuttling of TXNIP into mitochondria.

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IL-15 upregulates thioredoxin activity in NK cells and reduces shuttling...
(A) Heatmap of differential gene expression in GO (GO:000302) based on comparisons of IL-15– and IL-2–primed NK cells. (B) Representative histogram and relative MFI of thioredoxin (Trx1) in NK cells, normalized to the isotype control. (C) Maximum-intensity projections of confocal images (×63 objective) for NK cells treated with 10 μM H2O2 and primed with either IL-15 or IL-2. Blue (DAPI) shows staining of nuclei, green shows staining for TXNIP, and red shows staining of mitochondria. Scale bar: 10 μm. (D) Image quantification of TXNIP counts (green objects) per cell nucleus in NK cells with or without 10 mM H2O2 treatment. (E) Image quantification of TXNIP MFI (green fluorescence intensity) overlapping with mitochondria (red objects) in NK cells with or without 10 μM H2O2 treatment. *P < 0.05, **P < 0.01, and ****P < 0.0001, by Wilcoxon signed-rank test (B) and Kruskal-Wallis test (D and E). Data were pooled from 3 biological replicates and are represented as Tukey’s box plots.

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