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

Yang, Ying; Neo, Shi Yong; Chen, Ziqing; Cui, Weiyingqi; Chen, Yi; Guo, Min; Wang, Yongfang; Xu, Haiyan; Kurzay, Annina; Alici, Evren; Holmgren, Lars; Haglund, Felix; Wang, Kai; Lundqvist, Andreas

doi:10.1172/jci137585

Cited by 65 publications

(66 citation statements)

References 56 publications

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“…A recent study also reported that IL15-primed natural killer (NK) cells are shielded from oxidative stress, in which IL-15 boosts the TXN expression and reducing mitochondrial localization of TXN-interacting protein via mTOR activation. These IL-15-primed NK cells also present denser cell surface thiol groups for counteracting the ROS cytotoxicity [ 145 ]. In cultured muscle cells, H 2 O 2 -induced oxidative stress could be relieved by IL-15 pre-incubation [ 146 ].…”

Section: Myokines and Oxidative Stressmentioning

confidence: 99%

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle—Do Myokines Play a Role?

Pang¹,

Chan²,

Chan³

2021

Antioxidants

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Mitochondria are the cellular powerhouses that generate adenosine triphosphate (ATP) to substantiate various biochemical activities. Instead of being a static intracellular structure, they are dynamic organelles that perform constant structural and functional remodeling in response to different metabolic stresses. In situations that require a high ATP supply, new mitochondria are assembled (mitochondrial biogenesis) or formed by fusing the existing mitochondria (mitochondrial fusion) to maximize the oxidative capacity. On the other hand, nutrient overload may produce detrimental metabolites such as reactive oxidative species (ROS) that wreck the organelle, leading to the split of damaged mitochondria (mitofission) for clearance (mitophagy). These vital processes are tightly regulated by a sophisticated quality control system involving energy sensing, intracellular membrane interaction, autophagy, and proteasomal degradation to optimize the number of healthy mitochondria. The effective mitochondrial surveillance is particularly important to skeletal muscle fitness because of its large tissue mass as well as its high metabolic activities for supporting the intensive myofiber contractility. Indeed, the failure of the mitochondrial quality control system in skeletal muscle is associated with diseases such as insulin resistance, aging, and muscle wasting. While the mitochondrial dynamics in cells are believed to be intrinsically controlled by the energy content and nutrient availability, other upstream regulators such as hormonal signals from distal organs or factors generated by the muscle itself may also play a critical role. It is now clear that skeletal muscle actively participates in systemic energy homeostasis via producing hundreds of myokines. Acting either as autocrine/paracrine or circulating hormones to crosstalk with other organs, these secretory myokines regulate a large number of physiological activities including insulin sensitivity, fuel utilization, cell differentiation, and appetite behavior. In this article, we will review the mechanism of myokines in mitochondrial quality control and ROS balance, and discuss their translational potential.

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Section: Myokines and Oxidative Stressmentioning

confidence: 99%

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle—Do Myokines Play a Role?

Pang¹,

Chan²,

Chan³

2021

Antioxidants

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“…When encountered with abundant reactive oxidative species (ROS) in solid tumors, studies have shown that IL-15 stimulation upregulated the thioredoxin system in NK cells and T cells to confer increased tolerance towards oxidative stress [5,7]. As a complement, we found that IL-15 enhanced mTOR activity leading to higher levels of surface thiols on NK cells to neutralize extracellular ROS, compared with IL-2 [6]. Meanwhile, it has been reported that TGFβ could inhibit the activation and function of NK cells through curbing the IL-15-induced mTOR pathway [91].…”

Section: Immunomodulation Of T and Nk Cells In The Tumor Microenvironmentioning

confidence: 65%

“…It does not mediate AICD, but instead inhabits AICD induced by IL-2 [4]. In addition, recent studies have revealed the different ability of IL-2 and IL-15 to facilitate the activation and persistence of T and NK cells against various immune suppressive factors [5][6][7]. Their private receptor component, IL-2Rα or IL-15Rα, might contribute to these distinctive functions of IL-2 and IL-15, but further investigations are still required for better understanding of mechanism behind their differences.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy

Yang

Lundqvist

2020

Cancers

Self Cite

104

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The type I cytokine family members interleukin-2 (IL-2) and IL-15 play important roles in the homeostasis of innate and adaptive immunity. Although IL-2 and IL-15 receptor complexes activate similar signal transduction cascades, triggering of these receptors results in different functional activities in lymphocytes. While IL-2 expands regulatory T cells and CD4+ helper T cells, IL-15 supports the development of central memory T cells and NK cells. Recent data have provided evidence that IL-2 and IL-15 differ in their ability to activate T and NK cells to resist various forms of immune suppression. The diverse roles of these two cytokines have on immune cells lead to critical therapeutic implications for cancer treatment. In this review, we discuss the distinct roles of IL-2 and IL-15 in activating various functions in T and NK cells with a particular focus on the signals that participate in the resistance of tumor-derived immune suppressive factors. Furthermore, we summarize current clinical applications of IL-2 and IL-15 in metastatic malignancies, either as monotherapy or in combination with other agents, and highlight the future trends for research on these cytokine-based immunotherapies.

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“…Another study using sublethal doses of hematoporphyrin-based photodynamic therapy reached a similar conclusion based on elevated MIC A,B tumor cell expression in the context of ROS generation, and subsequently enhanced NK-cell-mediated killing [39]. However, it needs to be stressed that ROS severely impair NK-cell activity and survival, as IL-15-primed NK-cells upregulate thioredoxin activity to protect themselves from cytotoxic ROS in the tumor microenvironment (TME) [40]. This is in line with the notion that NK-cells are sensitive against ROS like hydrogen peroxide [41].…”

Section: Discussionmentioning

confidence: 89%

Physical Plasma-Treated Skin Cancer Cells Amplify Tumor Cytotoxicity of Human Natural Killer (NK) Cells

Clemen

Heirman

Lin

et al. 2020

Cancers

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Skin cancers have the highest prevalence of all human cancers, with the most lethal forms being squamous cell carcinoma and malignant melanoma. Besides the conventional local treatment approaches like surgery and radiotherapy, cold physical plasmas are emerging anticancer tools. Plasma technology is used as a therapeutic agent by generating reactive oxygen species (ROS). Evidence shows that inflammation and adaptive immunity are involved in cancer-reducing effects of plasma treatment, but the role of innate immune cells is still unclear. Natural killer (NK)-cells interact with target cells via activating and inhibiting surface receptors and kill in case of dominating activating signals. In this study, we investigated the effect of cold physical plasma (kINPen) on two skin cancer cell lines (A375 and A431), with non-malignant HaCaT keratinocytes as control, and identified a plasma treatment time-dependent toxicity that was more pronounced in the cancer cells. Plasma treatment also modulated the expression of activating and inhibiting receptors more profoundly in skin cancer cells compared to HaCaT cells, leading to significantly higher NK-cell killing rates in the tumor cells. Together with increased pro-inflammatory mediators such as IL-6 and IL-8, we conclude that plasma treatment spurs stress responses in skin cancer cells, eventually augmenting NK-cell activity.

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

Cited by 65 publications

References 56 publications

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle—Do Myokines Play a Role?

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle—Do Myokines Play a Role?

Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy

Physical Plasma-Treated Skin Cancer Cells Amplify Tumor Cytotoxicity of Human Natural Killer (NK) Cells

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