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 6

NK cell infiltration is influenced by the accumulation of oxidative stress in NSCLC tumors.

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NK cell infiltration is influenced by the accumulation of oxidative stre...
(A) Representative images of immunohistochemical staining for CD56 within immune infiltrates found in NSCLC tumor core and tumor periphery. Triangles indicate CD56+ lymphocytes. Scale bars: 50 μm (original magnification, ×40). n = 4. (B) Percentage of infiltrating NK cells in the different patient tissues collected (n = 16). (C) Percentage of ROShi NK cells in the different patient tissues collected (n = 16). (D–G) Correlation of ROShi NK cells with the percentage of infiltrating NK cells isolated in (D) pooled tissue samples (n = 48), (E) adjacent normal lung tissue (n = 16), (F) tumor periphery (n = 16), and (G) central tumor (n = 16). (B and C) All matching data points for autologous samples are connected with lines. **P < 0.01, ***P < 0.001, ****P < 0.0001, by Friedman’s test. (D–G) Spearman’s rank correlation coefficient test was used to determine significant correlations.