Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells
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
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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Research Article Immunology Oncology

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

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 5

mTOR suppresses TXNIP expression to sustain thioredoxin activity and surface thiol density.

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mTOR suppresses TXNIP expression to sustain thioredoxin activity and sur...
(A) Western blots of TXNIP protein expression in NK cells treated with Torin-1 (n = 3). (B) Concentration of active thioredoxin protein in NK cells primed with either IL-2 or IL-15 or with IL-15 plus Torin-1 treatment (n = 5). (C) MFI of thioredoxin-1 expressed in IL-12– or IL-15–primed NK cells with and without Torin-1 treatment (n = 5). (D) MFI of maleimide staining of IL-12– or IL-15–primed NK cells with and without Torin-1 treatment (n = 5). (E) Relative increased percentage of ROShi NK cells primed with either IL-2 or IL-15 and treated with Torin-1 after exposure to 10 μM H2O2 , compared with NK cells without H2O2 exposure (n = 6). (F) Representative maximum-intensity projections of confocal images (×63 objective) of NK cells treated with 1 mM Torin-1. Blue represents DAPI staining of the nucleus, green represents TXNIP staining, and magenta represents mitochondria staining. Scale bar: 10 μm. (G) MFI of TXNIP (green fluorescence intensity) within the nuclei of NK cells under H2O2 oxidative stress. (H) Image quantification of the cytoplasm/nucleus ratio of TXNIP MFI of NK cells under H2O2 oxidative stress. All individual data points are connected for matching replicates. Data were pooled from 3 biological replicates and are represented as Tukey’s box plots. *P < 0.05, **P < 0.01, and ***P < 0.001, by Friedman’s test (B), repeated-measures 2-way ANOVA with Holm-Šidák’s multiple-comparisons test (C–E), and Kruskal-Wallis test (G and H).