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Review
. 2016:2016:1580967.
doi: 10.1155/2016/1580967. Epub 2016 Jul 28.

Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment

Xinfeng Chen  1 , Mengjia Song  2 , Bin Zhang  3 , Yi Zhang  4
Affiliations
Review

Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment

Xinfeng Chen et al. Oxid Med Cell Longev. 2016.

Abstract

Reactive oxygen species (ROS) produced by cellular metabolism play an important role as signaling messengers in immune system. ROS elevated in the tumor microenvironment are associated with tumor-induced immunosuppression. T cell-based therapy has been recently approved to be effective for cancer treatment. However, T cells often become dysfunctional after reaching the tumor site. It has been reported that ROS participate extensively in T cells activation, apoptosis, and hyporesponsiveness. The sensitivity of T cells to ROS varies among different subsets. ROS can be regulated by cytokines, amino acid metabolism, and enzymatic activity. Immunosuppressive cells accumulate in the tumor microenvironment and induce apoptosis and functional suppression of T cells by producing ROS. Thus, modulating the level of ROS may be important to prolong survival of T cells and enhance their antitumor function. Combining T cell-based therapy with antioxidant treatment such as administration of ROS scavenger should be considered as a promising strategy in cancer treatment, aiming to improve antitumor T cells immunity.

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Figures

Figure 1
Figure 1
ROS produced in the tumor microenvironment. FasL ligation and TCR signaling in T cells could induce the production of ROS via NOX-2, DUOX-1, and mitochondria. Activated phagocytes (neutrophils, eosinophils, and mononuclear phagocytes) can produce large amounts of ROS by the NOX-2 during respiratory burst. Activated T cells can also induce respiratory burst by direct contacts with phagocytes or cytokines. TGF-β activates NOXs of Tregs, which trigger the production of ROS. Moreover, macrophage-derived ROS can induce Tregs accumulation in the tumor microenvironment. Mutations of mitochondrial DNA (mtDNA) in tumor cells result in a deficiency in respiratory complex I activity and contribute to the overproduction of ROS. MDSCs also produce amounts of ROS in the tumor microenvironment.
Figure 2
Figure 2
Multifaceted regulation of T cell responses by ROS. CD3 activation leads to rapid influx of calcium promoting ROS production. However, the connection between calcium and ROS production is under debate. Both signals are essential for TCR signaling. ROS trigger activation-induced cell death of T cells via Fas/FasL pathway. The low levels of mitochondrial ROS are required for T cell proliferation, while high levels of ROS inhibit NFAT5 by binding to IL-6 promoter and decrease T cell proliferation. Mitochondrial ROS are indispensable for T cell activation by regulating IL-2 and IL-4 secretion. Chronic exposure to ROS may inhibit NF-κB phosphorylation and activation, which induces T lymphocytes hyporesponsiveness. NOX-2 derived ROS increase IFN-γ production via increasing the levels of JNK and NF-κB phosphorylation, transcription factors STAT-1 and T-bet, and cytokines secretion of IL-2, IL-4, TNF-α, and GM-CSF. Further, NOX-2 derived ROS decrease phosphorylation of STAT3 and production of IL-10, TGF-β, and IL-17. Mitochondrial ROS regulate differentiation of Th17 cells and Th1 cells. Low levels of ROS induce the immunoregulatory enzyme, indoleamine 2,3-dioxygenase, and enhance the function of Tregs. NOX/ROS is a key upstream component of CD3 and CD28 signaling pathways during Tc1 cell development.
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References

    1. Dröge W. Free radicals in the physiological control of cell function. Physiological Reviews. 2002;82(1):47–95. doi: 10.1152/physrev.00018.2001. - DOI - PubMed
    1. Trachootham D., Alexandre J., Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Reviews Drug Discovery. 2009;8(7):579–591. doi: 10.1038/nrd2803. - DOI - PubMed
    1. Cornelissen C., Brans R., Czaja K., et al. Ultraviolet B radiation and reactive oxygen species modulate interleukin-31 expression in T lymphocytes, monocytes and dendritic cells. British Journal of Dermatology. 2011;165(5):966–975. doi: 10.1111/j.1365-2133.2011.10487.x. - DOI - PubMed
    1. Asano H., Horinouchi T., Mai Y., et al. Nicotine- and tar-free cigarette smoke induces cell damage through reactive oxygen species newly generated by PKC-dependent activation of NADPH oxidase. Journal of Pharmacological Sciences. 2012;118(2):275–287. doi: 10.1254/jphs.11166FP. - DOI - PubMed
    1. Ganeva M. G., Getova D. P., Gadjeva V. G. Adverse drug reactions and reactive oxygen species. Folia Medica. 2008;50(1):5–11. - PubMed

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