title: Upregulation of thioredoxin-1 in activated human NK cells confers increased tolerance to oxidative stress.
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 H2O2on 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.
authors.affiliation: Department of Surgery, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore.|Department of Surgery, Fujikawa Hospital, Kyonan Medical Center, 340-1 Kajikazawa, Fujikawa-cho, Minamikoma-gun, Yamanashi, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.affiliation: Department of Hematology-Oncology, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore.
authors.forename: Ley-Fang
authors.initials: LF
authors.lastname: Kua
authors.affiliation: Department of Pediatrics, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore.
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimasaki
authors.affiliation: Department of Surgery, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore.|Department of Surgery, Fujikawa Hospital, Kyonan Medical Center, 340-1 Kajikazawa, Fujikawa-cho, Minamikoma-gun, Yamanashi, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shiraishi
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore, Singapore.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore, Singapore.
authors.forename: Lim Kee
authors.initials: LK
authors.lastname: Siang
authors.affiliation: Department of Surgery, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore.
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.affiliation: Department of Surgery, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore.
authors.forename: Jimmy
authors.initials: J
authors.lastname: So
authors.affiliation: Department of Hematology-Oncology, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Department of Surgery, National University of Singapore, 1E Kent Ridge Road, Singapore, Singapore. kojikono@fmu.ac.jp.|Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore, Singapore. kojikono@fmu.ac.jp.|Department of Organ Regulatory Surgery and Advanced Cancer Immunotherapy, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan. kojikono@fmu.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000494:pharmacology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D018384:Oxidative Stress / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology; D013879:Thioredoxins / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D057134:Antibodies, Neutralizing; D007376:Interleukin-2; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013879:Thioredoxins; D006861:Hydrogen Peroxide
keywords: Hydrogen Peroxide; IL-2; Immune surveillance; NK cells; Thioredoxin-1