Immunopharmacology of Free Radical Species (Handbook of Immunopharmacology)
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Advances in immunopharmacology in China. International Journal of Immunopharmacology 10 Supp-S1 : , Recent advances in immunopharmacology. Yao Xue Xue Bao 22 1 : , Immunopharmacology of asthma. Trends in Pharmacological Sciences 14 5 : , The immunopharmacology of mild asthma.
The Handbook of Immunopharmacology Immunopharmacology of free radical species. Recent advances in the preclinical and clinical immunopharmacology of interleukin emphasis on IL-2 as an immunorestorative agent. Cancer Detection and Prevention 12 : , The Handbook of Immunopharmacology Immunopharmacology of the gastrointestinal system.
The Handbook of Immunopharmacology Immunopharmacology of platelets. Immunopharmacology of the Heart The Handbook of Immunopharmacology. Cardiovascular Research 28 9 : , Asthma: Physiology, immunopharmacology and treatment edited by A. Barry Kay, K. Reactive oxygen species ROS are small short-live oxygen-containing molecules that are chemically highly reactive. In addition, there are also other exogenous sources of ROS, including ultraviolet and gamma radiation, air pollutants, and chemicals [ 3 — 5 ]. Moreover, H 2 O 2 reacts with thiols at a physiological concentration and forms disulfide bond [ 9 ].
Thus, H 2 O 2 can act as a second messenger because of the following: i it has relative long half-life, ii it is uncharged, iii it can cross membranes, iv it is relatively specific thiols , and the modifications disulfide bonds are reversible [ 10 ]. H 2 O 2 has been reported to participate in many processes, such as cell growth, stem cell renewal, tumorigenesis, cell death, cell senescence, cell migration, oxygen sensing, angiogenesis, circadian rhythm maintenance, myofibroblasts differentiation, and immune responses [ 7 , 11 — 16 ]. ROS elevated in almost all cancers act as a double-edged sword during tumor development [ 17 ].
ROS levels are also associated with cancer cell stemness [ 18 ]. It has been demonstrated that immunosuppressive tumor microenvironment facilitates tumor invasion, metastasis, and resistance [ 19 ]. ROS are likely immunosuppressive participants in tumor progression [ 20 ]. Indeed, ROS production greatly contributes to inhibitory activities of tumor-induced-immunosuppressive cells [ 21 , 22 ]. Therefore, ROS are not only mediators of oxidative stress, but also players of immune regulation during tumor development.
ROS-mediated signaling can be additionally regulated via altering local concentrations e. ROS are essential particularly at low levels for a wide range of innate immune functions, including antiviral, antibacterial, and antitumor responses [ 24 ]. This review will mainly discuss the production of ROS in the tumor microenvironment and the impact on antitumor T cell immune response. As shown in Figure 1 , ROS produced by cancer cells and tumor-infiltrating leukocytes, including myeloid-derived suppressor cells MDSCs , tumor-associated macrophages TAMs , and regulatory T cells Tregs , can suppress the immune responses.
ROS produced in the tumor microenvironment.
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. Moreover, macrophage-derived ROS can induce Tregs accumulation in the tumor microenvironment.
It has been revealed that MDSCs, as one of the major immunosuppressive subsets, play a pivotal role in promoting tumor progression and contribute to suppressive tumor microenvironment by producing ROS [ 25 , 26 ]. In addition, scavenging of H 2 O 2 with catalase induces differentiation of immature myeloid into macrophages in tumor-bearing mice, suggesting that ROS also play an important role in maintaining the undifferentiated state of MDSC [ 32 , 33 ].
TAMs are considered as critical links between inflammation and cancer development [ 35 , 36 ]. ROS produced by macrophages have been reported to have immunosuppressive properties and could also be functional for induction of Tregs [ 37 ]. The ROS producing capacity by different subtypes of macrophages is discrepant. In contrast, CD, a costimulatory immune checkpoint molecule, could reduce typical macrophage characteristics such as phagocytosis, oxidative burst, and CD14 expression, which could induce the differentiation of monocytes to dendritic cells DC and DC maturation and reduce ROS generation [ 39 ].
Indeed, peripheral blood T lymphocytes from cancer patients showed an increased ROS production compared to those from healthy subjects [ 42 ]. The process of TCR activation is accompanied by ROS production, and tumor-infiltrating lymphocytes could be dysfunctional due to the ROS accumulated in the tumor microenvironment. Intracellular ROS level in T cells is tightly regulated through NOX-2, dual-substrate oxidase 1 DUOX-1 , mitochondria, and the expression of a variety of antioxidant systems, including superoxide dismutase, peroxiredoxins, and glutaredoxins coupled to metabolic status of T cells [ 43 — 45 ].
Mitochondria generate low amounts of ROS superoxides in a controlled and stimulation-dependent fashion, thereby less likely to have a direct influence on tumor cells or other surrounding cells. However, high amounts of extracellular ROS produced by an oxidative burst from macrophages or in a pathophysiological condition induce the disability of T cells [ 38 , 47 ].
Tregs are key immunosuppressive cells increased in cancer patients. Low level of ROS has been also shown to induce the immunoregulatory enzyme, indoleamine 2,3-dioxygenase, and enhance the function of Tregs [ 50 ].
Indeed, Tregs isolated from neutrophil cytosolic factor 1 Ncf1 deficiency mice with a lower level of ROS were hyporeactive compared to those from wild type mice [ 50 ]. Other inflammatory cells such as neutrophils, eosinophils, and mononuclear phagocytes could produce ROS in the tumor microenvironment as well [ 51 ], thereby contributing to tumor growth and antitumor immune response. Besides immune cells in the tumor microenvironment, tumor cells could also generate excessive ROS [ 42 ], which may be encoded from mutations of electron transport chain ETC mitochondria-related genes as well as the mitochondrial DNA damage.
ROS generated by mitochondria contribute to the initiation of nuclear of mitochondrial DNA mutations that promote neoplastic transformation [ 53 ]. ROS in cancer cells can be also driven by increased metabolism, oncogene activity, and abnormal expression of NOXs and play a doubled-edged sword role in cancer progression.
The dual roles of ROS depend on their concentration [ 54 ]. On one hand, ROS could facilitate carcinogenesis and cancer progression at mild-to-moderate elevated levels. Metabolic synergy or metabolic coupling between glycolytic stromal cells Warburg effect and oxidative cancer cells occur in cancer and promote tumor growth, while ROS are key mediators of the stromal Warburg effect [ 55 ]. On the other hand, excessive ROS would damage cancer cells dramatically and even lead to cell death [ 54 , 56 ]. Tumor cells can express increased levels of antioxidant proteins to detoxify ROS [ 57 ].
Nuclear factor erythroid 2-related factor 2 Nrf2 is a pivotal transcription preventing oxidative stress, but aberrant activation of Nrf2 often occurs in various human cancers. In contrast, capsaicin mediates bladder cancer cell death through increasing ROS production [ 59 ]. Indeed, activities of MMP-2 and MMP-9 in tumor tissues were correlated with superoxide radicals generation rate [ 63 ]. Taken together, considering dual roles of ROS, the strategies of decreasing or increasing the level of ROS in cancer cells warrant cautious consideration for cancer treatment.
During the process of ROS production, the level of ROS is usually regulated by many factors in the tumor microenvironment. MMPs have been identified as important regulators of the activity of mitochondrial respiratory chain and intracellular ROS production [ 71 ]. Third, ROS generation was associated with cell metabolism and glucose metabolism and mitochondrial respiratory would increase ROS production [ 49 , 72 ]. In addition, Calnexin expression is required for cellular NOX4 protein expression and ROS formation [ 73 ], which may regulate cell apoptosis induced by endoplasmic reticulum stress or by inositol starvation [ 74 , 75 ].
Camalexin induced T-leukemia Jurkat cell apoptosis by increasing ROS concentration and activation of caspase-8 and caspase-9 [ 76 ]. Several chemotherapeutic agents, such as Chelerythrine protein kinase C inhibitor and Quinones, also induced tumor cells apoptosis through increasing ROS [ 77 , 78 ]. Level of ROS is dynamic and regulated by antioxidant system in the body. Antioxidant mechanisms, either enzymatic catalases, dismutases, and peroxidases or nonenzymatic vitamins A, C, and E and GSH , are critical to protect cells against ROS-induced damage [ 1 ].
ROS-mediated signaling can be opposed by specific antioxidants. For example, GSH, a major intracellular redox molecule that protects cells from oxidative stress [ 79 ], is essential for optimal T cell proliferation and activation, and it is synthesized by cysteine [ 80 ]. Inactivation of the extracellular superoxide dismutase SOD leads to accumulation of ROS in the tumor microenvironment [ 81 ].
Silencing MnSOD results in increasing intracellular oxidative stress, while increasing MnSOD exerts an antitumor effect both in vitro and in vivo [ 82 ].
ROS excessive in the tumor microenvironment reduce antitumor function and proliferation of T cells and increase T cell apoptosis. ROS produced by other cells can reach T cells and cause oxidative stress which may induce T cell hyporesponsiveness in cancer patients [ 83 ]. It has been reported that exposure of T cells to high level ROS downregulates T cell activity [ 84 ]. Though exact effect of ROS on T cells function remains unclear, the balance between production and consumption of ROS is an important factor that determines the T cell apoptosis, activation, differentiation, proliferation, and function Figure 2.
Indeed, ROS at a low-concentration are essential for T cell activation, expansion, and effector function [ 34 , 44 ]. 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.
CD6 | CD molecules | IUPHAR Guide to IMMUNOPHARMACOLOGY
Both signals are essential for TCR signaling. Low levels of ROS induce the immunoregulatory enzyme, indoleamine 2,3-dioxygenase, and enhance the function of Tregs. TCR signaling pathways are affected differentially by physiological levels of ROS that trigger several proximal and distal signaling pathways in T cells. CD3 activation leads to rapid influx of calcium, in turn regulating ROS production [ 49 ], while Devadas shows that calcium release is essential for ROS production [ 34 ].
However, both signals are essential for T cell receptor signaling [ 85 ].
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Mitochondrial ROS control T cell activation by regulating IL-2 and IL-4 expression, which are determined by an oxidative signal originating from mitochondrial respiratory complex I [ 87 ]. Moreover, recently it has been shown that retrograde electron flow and ROS production were important not only in T cell activation but also in aging and development of Parkinson disease [ 88 , 89 ].
For another, Granzyme B secreted by cytotoxic T cells induces proapoptotic pathways and then leads to cell death [ 98 ]. ROS produced by extramitochondria are involved in the process of Granzyme B induced cell death, most probably through activation of NOX [ 99 ]. Indeed, specific mitochondria ROS inhibitors such as N-acetylcysteine and mitoquinone reduced production of Th17 cells [ ], whereas mitochondrial ROS were historically thought to be primarily cytotoxic by directly damaging DNA, lipids, and proteins [ ].
Moreover, gene IEX-1 deficiency facilitated Th17 cell differentiation during early responses, which was mediated by increased formation of ROS at mitochondria following T cell activation [ ]. Programmed death-1 PD-1 is described initially as a marker of apoptosis and is considered as a checkpoint that controls T cell function. PD-1 blockade has been recently approved to treat patients with advanced-stage cancers by enhancing antitumor T cell immunity [ ].
Immunopharmacology of Free Radical Species
As the expression level of PD-1 is correlated with production of cellular ROS and oxidative metabolism [ ], it would be interesting to explore potential strategies of combining ROS scavenger with PD-1 signaling blockade for rapid clinical translation. The susceptibility of human T cells to H 2 O 2 -induced apoptosis strongly varies among T cell subsets.
It is likely that effector T cells are most insensitive to ROS-mediated death. Several studies have shown that GSH plays essential roles in increasing T cell function and proliferation [ 15 , ], while ROS scavenger could reduce ROS-induced apoptosis of naive and memory cells. Furthermore, a correlation between intracellular GSH depletion and progression of apoptosis has been confirmed in several studies [ — ]. Additionally, high GSH levels are associated with an apoptotic resistant phenotype in different cells.
In addition, oxidative stress is a central regulator of HMGB1 translocation, release, and activity [ ]. ROS produced mainly by tumor cells and immunosuppressive cells in the tumor microenvironment may determine the activation, proliferation, differentiation, and apoptosis of antitumor T cells. Considering the ROS-mediated immunosuppressive mechanisms, an important implication of therapeutic strategy targeting ROS is using antioxidant agents or supplements which may regulate antitumor T cell responses. Specifically, T cell-based therapy combined with ROS scavenger would improve clinical efficacy by enhancing expansion and function of antitumor T cells.
Despite remarkable progress in recent years, the mechanism for the roles of ROS in T cell biology still remains unclear. Development of more effective strategies combining ROS manipulation and T cell-based therapy warrants further investigations particularly for the treatment of patients with advanced cancer. National Center for Biotechnology Information , U. Oxid Med Cell Longev. Published online Jul Author information Article notes Copyright and License information Disclaimer.
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Reactive oxygen species ROS produced by cellular metabolism play an important role as signaling messengers in immune system.
Introduction Reactive oxygen species ROS are small short-live oxygen-containing molecules that are chemically highly reactive. Open in a separate window. Figure 1. Figure 2. Conclusions and Perspectives ROS produced mainly by tumor cells and immunosuppressive cells in the tumor microenvironment may determine the activation, proliferation, differentiation, and apoptosis of antitumor T cells.
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