Cancer Immunology, Immunotherapy

, Volume 66, Issue 5, pp 605–613 | Cite as

Upregulation of thioredoxin-1 in activated human NK cells confers increased tolerance to oxidative stress

  • Kousaku Mimura
  • Ley-Fang Kua
  • Noriko Shimasaki
  • Kensuke Shiraishi
  • Shotaro Nakajima
  • Lim Kee Siang
  • Asim Shabbir
  • Jimmy So
  • Wei-Peng Yong
  • Koji Kono
Original Article
First Online:
Received:
Accepted:

Abstract

Adoptive transfer of immune cells, such as T lymphocytes and NK cells, has potential to control cancer growth. However, this can be counteracted by immune escape mechanisms within the tumor microenvironment, including those mediated by reactive oxygen species (ROS). Here, we determined the levels of anti-oxidant molecules in NK cells and their capacity to overcome ROS-induced immune suppression. We investigated the effect of H2O2 on resting NK cells, IL-2-activated NK cells and NK cells expanded by coculture with the K562 leukemia cell line genetically modified to express membrane-bound IL-15 and 4-1BB ligand (K562-mb15-41BBL). Expression of anti-oxidant and anti-apoptotic genes was evaluated by expression array, and protein levels of anti-oxidant molecules by Western blot. Activated NK cells, IL-2-activated NK cells and NK cells expanded by K562-mb15-41BBL were significantly more resistant to H2O2-induced cell death than resting NK. Thioredoxin-1 (TXN1) and peroxiredoxin-1 (PRDX1) were also up-regulated in activated NK cells. Moreover, H2O2-induced cell death after IL-2 activation was significantly induced in the presence of an anti-TXN1-neutralising antibody. Collectively, these data document that activated NK cells can resist to H2O2-induced cell death by up-regulation of TXN1.

Keywords

IL-2 NK cells Thioredoxin-1 Hydrogen Peroxide Immune surveillance 

Abbreviations

7-AAD

7-Aminoactinomycin D

Akt

Protein kinase B

ECL

Enhanced chemiluminescence

Erk

Extracellular signal–regulated kinase

Expanded NK

NK cells expanded with K562 leukemia cell line genetically modified to express membrane-bound IL-15 and 4-1BB ligand for 7 days

IL-2 NK

NK cells activated by several doses of IL-2 for 7 days

K562-mb15-41BBL

K562 leukemia cell line genetically modified to express membrane-bound IL-15 and 4-1BB ligand

PRDX1

Peroxiredoxin-1

Resting NK

Resting NK cells

ROS

Reactive oxygen species

SOD

Superoxide dismutase

TXN1

Thioredoxin-1

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Notes

Acknowledgements

This work was supported by a Clinician Scientist Award (CSA) and Clinician Scientist-Individual Research Grant (CS-IGR) from the National Medical Research Council of Singapore. We would like to thank Dr. Dario Campana (National University of Singapore, Singapore) for providing us with the K562-mb15-41BBL cell line.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Kousaku Mimura
    • 1
    • 5
  • Ley-Fang Kua
    • 2
  • Noriko Shimasaki
    • 3
  • Kensuke Shiraishi
    • 1
    • 5
  • Shotaro Nakajima
    • 4
  • Lim Kee Siang
    • 4
  • Asim Shabbir
    • 1
  • Jimmy So
    • 1
  • Wei-Peng Yong
    • 2
  • Koji Kono
    • 1
    • 4
    • 6
  1. 1.Department of SurgeryNational University of SingaporeSingaporeSingapore
  2. 2.Department of Hematology-OncologyNational University of SingaporeSingaporeSingapore
  3. 3.Department of PediatricsNational University of SingaporeSingaporeSingapore
  4. 4.Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
  5. 5.Department of Surgery, Fujikawa HospitalKyonan Medical CenterYamanashiJapan
  6. 6.Department of Organ Regulatory Surgery and Advanced Cancer ImmunotherapyFukushima Medical UniversityFukushima CityJapan

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