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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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 4

Inhibition of thioredoxin-1 reduces NK cell surface thiol groups and reverses IL-15–mediated resistance to oxidative stress.

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Inhibition of thioredoxin-1 reduces NK cell surface thiol groups and rev...
(A) MFI of maleimide staining on NK cells treated with PX-12 within IL-2– and IL-15–primed NK cell cultures (n = 6). (B) Percentage of increased ROShi NK cells after 10 μM H2O2 treatment compared with untreated NK cells in the presence or absence of PX-12 in IL-2 and IL-15 cultures (n = 6). (C) Relative increase in CellROX MFI in NK cell cocultures with or without PX-12 treatment, normalized to the control group without neutrophils (n = 6). (D) Relative fold-change of Ki-67 expression in NK cell cocultures with or without PX-12 treatment (n = 7). (E) Bright-field images of H1299 tumor spheres with green fluorescence–labeled NK cells. Images were acquired under a ×10 objective at 3 different time points. Scale bars: 400 mm. Vertical labels describe the pretreatment conditions of NK cells before coculture. (F) Percentage of infiltrating NK cells in tumor spheres with different NK cell pretreatments (n = 5). (G) Percentage of infiltrating NK cells in tumor spheres in FACS-sorted NK cells, based on maleimide staining (n = 4). All individual data points are connected for matching replicates. *P < 0.05, **P < 0.01, and ***P < 0.001, by repeated-measures 2-way ANOVA with Holm-Šidák’s multiple-comparisons test (A and B), Wilcoxon signed-rank test (for significance within IL-2 cultures) and Friedman’s test (for significance within IL-15 cultures) (C), Friedman’s test (D and F), and paired t test (G).