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
View: Text | PDF
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

×

Figure 3

NK cells express surface thiol groups to overcome oxidative stress and sustained cytotoxicity function.

Options: View larger image (or click on image) Download as PowerPoint
NK cells express surface thiol groups to overcome oxidative stress and s...
(A) Representative histogram and relative MFI of maleimide staining comparing IL-2– and IL-15–primed NK cell cultures (n = 6). (B) Relative MFI of maleimide staining comparing cells with 1 hour of H2O2 treatment in both IL-2– and IL-15–primed NK cell cultures (n = 5). (C) Relative MFI of intracellular ROS based on CellROX staining normalized to maleimidelo NK cells (n = 4). (D) Percentage of specific killing of K562 target cells at a 5:1 E/T ratio, with effector NK cells presorted on the basis of maleimide staining (n = 4). (E) t-SNE analysis of NK cells based on surface thiol density (maleimidehi vs. maleimidelo) and its phenotypes acquired by flow cytometry. (F) Representative ×63 maximum-intensity projections of TXNIP localization within NK cells sorted by surface density and relative quantification of TXNIP in cytoplasm versus the nucleus. Green shows TXNIP staining and blue shows DAPI staining of the nucleus. Scale bars: 10 μm. Data were pooled from 3 biological replicates and are represented as Tukey’s box plots. All Individual data points are presented as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by Mann-Whitney U test (A and F), repeated-measures 2-way ANOVA with Holm-Šidák’s multiple-comparisons test (B and D), and ordinary 2-way ANOVA with Tukey’s test for multiple-comparisons (C).