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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.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC7524507 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Yang Ying Y   Neo Shi Yong SY   Chen Ziqing Z   Cui Weiyingqi W   Chen Yi Y   Guo Min M   Wang Yongfang Y   Xu Haiyan H   Kurzay Annina A   Alici Evren E   Holmgren Lars L   Haglund Felix F   Wang Kai K   Lundqvist Andreas A  

The Journal of clinical investigation 20201001 10


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 prote  ...[more]

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