Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress

Citation: Andrés, C.M.C.; Pérez de la Lastra, J.M.; Juan, C.A.; Plou, F.J.; Pérez-Lebeña, E. Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress. Vaccines 2023,11, 218. https://doi.org/10.3390/ vaccines11020218 Academic Editor: Yashdeep Phanse Received: 14 December 2022 Revised: 14 January 2023 Accepted: 17 January 2023 Published: 19 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Review Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress Celia María Curieses Andrés1, JoséManuel Pérez de la Lastra 2,* , Celia Andrés Juan 3, Francisco J. Plou 4 and Eduardo Pérez-Lebeña 5 1Hospital Clínico Universitario of Valladolid, Avenida de Ramón y Cajal 3, 47003 Valladolid, Spain 2Cinquima Institute and Department of Organic Chemistry, Faculty of Sciences, Valladolid University, Paseo de Belén 7, 47011 Valladolid, Spain 3Institute of Natural Products and Agrobiology, CSIC-Spanish Research Council, Avda. Astrofísico Fco. Sánchez, 3, 38206 La Laguna, Spain 4Institute of Catalysis and Petrochemistry, CSIC-Spanish Research Council, 28049 Madrid, Spain 5Sistemas de Biotecnología y Recursos Naturales, 47625 Valladolid, Spain *Correspondence: jm.per[email protected] Abstract: Myeloid-derived suppressor cells MDSCs are a heterogeneous population of cells that expand beyond their physiological regulation during pathologies such as cancer, inflammation, bacterial, and viral infections. Their key feature is their remarkable ability to suppress T cell and natural killer NK cell responses. Certain risk factors for severe COVID-19 disease, such as obesity and diabetes, are associated with oxidative stress. The resulting inflammation and oxidative stress can negatively impact the host. Similarly, cancer cells exhibit a sustained increase in intrinsic ROS generation that maintains the oncogenic phenotype and drives tumor progression. By disrupting endoplasmic reticulum calcium channels, intracellular ROS accumulation can disrupt protein folding and ultimately lead to proteostasis failure. In cancer and COVID-19, MDSCs consist of the same two subtypes (PMN-MSDC and M-MDSC). While the main role of polymorphonuclear MDSCs is to dampen the response of T cells and NK killer cells, they also produce reactive oxygen species ROS and reactive nitrogen species RNS. We here review the origin of MDSCs, their expansion mechanisms, and their suppressive functions in the context of cancer and COVID-19 associated with the presence of superoxide anion •O2−and reactive oxygen species ROS. Keywords: myeloid-derived suppressor cells; cancer; COVID-19; reactive species; ROS; RNS and RHS; innate immunity; antimicrobial 1. Introduction Myeloid-derived suppressor cells MDSCs are formed from bone marrow progenitor cells when myelopoietic processes are disrupted by various diseases. They proliferate under pathological conditions due to altered hematopoiesis. They differ from other myeloid cell types in that they exhibit immunosuppressive activity, as opposed to immunostimulatory properties, and interact with and even regulate the functions of other immune cells, such as T cells, dendritic cells, macrophages, and natural killer cells NK. These MDSCs regulate the immune system and related responses associated with various diseases. Excessive production of these MDSCs is considered an important factor in the success or failure of cancer immunotherapy. Elevated levels of MDSCs in the tumor microenvironment TME correlate with poorer survival in patients with solid tumors and may mediate resistance to checkpoint inhibitor therapy CIT. Although their main function is to suppress the response of T cells and NK killer cells, polymorphonuclear MDSCs can generate reactive oxygen species ROS and reactive nitrogen species RNS. The accumulation of excessive intracellular ROS can cause stress to protein folding by altering endoplasmic reticulum calcium channels, thereby disrupting cell homeostasis. One of the Vaccines 2023,11, 218. https://doi.org/10.3390/vaccines11020218 https://www.mdpi.com/journal/vaccines Vaccines 2023,11, 218 2 of 22 main mechanisms by which MDSCs induce immune suppression is mediated by reactive oxygen species ROS. Increased ROS release in MDSCs is caused by augmented activity of NADPH oxidase NOX2 [ 1 ]. In this article, we review the function of MDSCs in cancer and COVID-19 disease. 2. Myeloid-Derived Suppressor Cells MDSC and Its Role in Immune System Under physiological conditions, myeloid progenitor cells differentiate into macrophages M, dendritic cells DC, or granulocytes G [ 2 ]. MDSCs are formed from bone marrow precursors when myelopoietic processes are disrupted, which occur when various diseases are triggered [ 3 ]. Under certain pathological conditions, such as in cancer or infection, myelopoiesis (defined as the production of the bone marrow and the resulting cells: eosinophilic granulocytes, basophilic granulocytes, neutrophilic granulocytes, and monocytes) is abnormal, allowing the accumulation and proliferation of immature myeloid cells that have potent immunosuppressive capabilities [ 4 – 7 ]. MDSCs were described more than 30 years ago in cancer patients [ 8 ]. Common features of MDSCs are their myeloid origin, their immature state and a remarkable ability to suppress T-cell and NK-cell responses [ 9 ]. MDSCs are elevated in virtually all patients with cancer and malignancies, and include two main subpopulations of cells: monocytic M-MDSC and granulocytic (polymorphonuclear PMN-MDSC), defined by their expression of plasma membrane markers and their content of immunosuppressive molecules [ 10 ]. MDSCs are pathologically activated neutrophils and monocytes and have potent immunosuppressive activity, regulating immune responses in many pathological conditions (including cancer, chronic infection, sepsis, and autoimmunity) and are closely associated with poor prognosis in cancer. MDSCs are a major obstacle to immunotherapies, as accumulation of MDSC populations in circulating leukocytes and tumor infiltrates has been observed in patients who do not respond to checkpoint inhibitor therapy [11,12]. In addition to their suppressive effects on adaptive immune responses, MDSCs regulate innate immune responses by modulating macrophage cytokine production [ 13 ]. Non-immunological functions of MDSCs, such as the promotion of tumor angiogenesis and metastasis, have also been described [ 14 ]. In pregnancy and neonates, the functions of MDSCs have been described under physiological conditions [15]. MDSCs are multifaceted and use multiple mechanisms to inhibit both adaptive and innate immunity; for example, in the adaptive system, T cells are a primary target. Initial studies showed that MDSCs produce some of their suppressive effects by releasing soluble mediators [ 16 ], requiring cell contact due to the short half-life and distribution of the effector molecules. On the one hand, infiltrating T cells are reduced in the tumor microenvironment [ 17 ], and at the same time MDSCs limit the migration of T cells to lymph nodes where they could be activated. Recent studies have shown that suppressive activity is also mediated by MDSC-derived exosomes [18]. Activation of MDSCs is mediated by the expression of inflammatory cytokines, such as GM-CSF, IL-6, G-CSF, IL-1 β , PGE2, TNFα , and VEGF and by transcriptional regulators including STAT3, CEBP/ β , STAT5, IRF8, S100A8/9, RB, TIPE2, and GCN2 [ 4 – 6 , 19 ]. Growing tumors produce cytokines and other substances that affect the development of MDSC, such as colony-stimulating factors G-CSF and GM-CSF and the MDSC-promoting interleukin IL-6 [20]. Recent results in both tumor mice and cancer patients suggest that increased metabolism of ARG1 by MDSCs inhibits T-cell responses [ 21 ]. MDSCs prevent T-cell activation by limiting the availability of amino acids necessary for T-cell proliferation, such as arginine, or by producing substances that block antigen recognition. MDSCs produce arginase 1 ARG1, which competes for the substrate arginine, depleting it, resulting in the loss of the T-cell receptor chain essential for T-cell activation. The main targets of MDSCs are T cells and the main factors involved in immune suppression include ARG1 arginase, iNOS, TGFβ , IL-10, COX2, cysteine sequestration by indoleamine 2,3-dioxygenase IDO, decreased L-selectin expression by T cells, and several others. M-MDSCs and PMN-MDSCs use different immune Vaccines 2023,11, 218 3 of 22 suppression mechanisms, the former M-type suppress T-cell responses both specifically and non-specifically using mechanisms associated with • NO and cytokine production [ 22 ]. PMN-MDSCs can suppress immune responses primarily in an antigen-specific manner and ROS production is essential to maintain this ability [ 23 ]. Extravasation of T cells from the blood and lymphatics to the lymph nodes requires the expression of L-selectin/CD62L on T cells. MDSCs express the enzyme ADAM-17, which cleaves L-selectin on T cells, thus preventing extravasation and limiting T-cell entry into lymph nodes [24]. NK-cell cytotoxicity is also inhibited by MDSC [ 25 ]. A novel subset of MDSCs specifically targeting NK cells is accumulated in the tumor microenvironment of mice by the proinflammatory cytokine IL-1. Upon their activation by prostaglandin E2 PGE2, MDSCs reduce NK-cell activity in melanoma patients by producing the immunosuppressive transforming growth factor, TGF-1β[26]. Dendritic cells DC are negatively affected by MDSC in a similar way [ 27 ], by the suppression of antigen presentation by type 1-T helper cells Th1 [ 28 ]. IL-10 and interferon IFNγ are required for the development of T regulatory cells Tregs, where ARG1 and CD40 play a role in this process. MDSC can alter the production of cytokines. Mice with tumors have decreased IL-7 and STAT5 signaling, which is important for B-cell differentiation, resulting in decreased circulating IgG levels. The population of tumor-associated macrophages (TAMs) promotes tumor progression. M-MDSC-derived macrophages retained most of the properties of their predecessors, including immunosuppressive function [ 29 ]. In hypoxic regions of solid tumors, M-MDSCs rapidly convert to TAMs and MDSCs also communicate with macrophages to enhance the protumoral activity of TAMs [30]. STAT3 is a repressor of anti-tumor immunity, and its expression impairs antigen presentation and inhibits the production of immunostimulatory cytokines, while promoting the expression of immunosuppressive molecules. This factor is present in most cancers and induces the production of inflammatory cytokines and growth factors such as IL-6, IL-10, IL23, LIF, VEGF, and HGF [ 31 – 33 ]. When STAT3 activation is induced in myeloid precursors, this factor controls cell survival, transcription of immunosuppressive enzymes (ARG1 and iNOS), prevents myeloid-cell maturation and results in aberrant differentiation into immature MDSCs [ 34 ]. Some of the key regulators of MDSC accumulation and activity are the transcription factors STAT3 and NFκβ . STAT3 enhances MDSC accumulation through several pathways. STAT3 and STAT5 inhibit IRF8, a crucial transcription factor that drives normal myeloid differentiation into monocytes and dendritic cells, and down-regulates the differentiation of MDSCs, when this is necessary to inhibit their pathological expansion [ 35 ]. The proinflammatory damage-associated molecular pattern DAMP is commonly found in the TME and activates MDSC through NF-κβ. STAT3 upregulates p47 phox and gp 91 , which increases • NO and peroxynitrite [ 1 ]. Peroxynitrite is formed when nitric oxide • NO reacts with superoxide anion • O 2− [ 1 ] due to the overexpression of two subunits of NADPH oxidase, p47 phox and gp 91 (derived from phosphorylation of STAT3, a hallmark of MDSC) [ 32 ]. Peroxynitrite is an anion derived from the reaction of •NO with •O2−, Figure 1. Vaccines 2023, 11, x FOR PEER REVIEW 3 of 22 TGF-β, IL-10, COX2, cysteine sequestration by indoleamine 2,3-dioxygenase IDO, decreased L-selectin expression by T cells, and several others. M-MDSCs and PMN-MDSCs use different immune suppression mechanisms, the former M-type suppress T-cell responses both specifically and non-specifically using mechanisms associated with •NO and cytokine production [22]. PMN-MDSCs can suppress immune responses primarily in an antigen-specific manner and ROS production is essential to maintain this ability [23]. Extravasation of T cells from the blood and lymphatics to the lymph nodes requires the expression of L-selectin/CD62L on T cells. MDSCs express the enzyme ADAM-17, which cleaves L-selectin on T cells, thus preventing extravasation and limiting T-cell entry into lymph nodes [24]. NK-cell cytotoxicity is also inhibited by MDSC [25]. A novel subset of MDSCs specifically targeting NK cells is accumulated in the tumor microenvironment of mice by the proinflammatory cytokine IL-1. Upon their activation by prostaglandin E2 PGE2, MDSCs reduce NK-cell activity in melanoma patients by producing the immunosuppressive transforming growth factor, TGF-1β [26]. Dendritic cells DC are negatively affected by MDSC in a similar way [27], by the suppression of antigen presentation by type 1-T helper cells Th1 [28]. IL-10 and interferon IFN-γ are required for the development of T regulatory cells Tregs, where ARG1 and CD40 play a role in this process. MDSC can alter the production of cytokines. Mice with tumors have decreased IL-7 and STAT5 signaling, which is important for B-cell differentiation, resulting in decreased circulating IgG levels. The population of tumor-associated macrophages (TAMs) promotes tumor progression. M-MDSC-derived macrophages retained most of the properties of their predecessors, including immunosuppressive function [29]. In hypoxic regions of solid tumors, M-MDSCs rapidly convert to TAMs and MDSCs also communicate with macrophages to enhance the protumoral activity of TAMs [30]. STAT3 is a repressor of anti-tumor immunity, and its expression impairs antigen presentation and inhibits the production of immunostimulatory cytokines, while promoting the expression of immunosuppressive molecules. This factor is present in most cancers and induces the production of inflammatory cytokines and growth factors such as IL-6, IL-10, IL-23, LIF, VEGF, and HGF [31–33]. When STAT3 activation is induced in myeloid precursors, this factor controls cell survival, transcription of immunosuppressive enzymes (ARG1 and iNOS), prevents myeloid-cell maturation and results in aberrant differentiation into immature MDSCs [34]. Some of the key regulators of MDSC accumulation and activity are the transcription factors STAT3 and NF-κβ. STAT3 enhances MDSC accumulation through several pathways. STAT3 and STAT5 inhibit IRF8, a crucial transcription factor that drives normal myeloid differentiation into monocytes and dendritic cells, and down-regulates the differentiation of MDSCs, when this is necessary to inhibit their pathological expansion [35]. The proinflammatory damage-associated molecular pattern DAMP is commonly found in the TME and activates MDSC through NF-κβ. STAT3 upregulates p47phox and gp91, which increases •NO and peroxynitrite [1]. Peroxynitrite is formed when nitric oxide •NO reacts with superoxide anion •O2− [1] due to the overexpression of two subunits of NADPH oxidase, p47phox and gp91 (derived from phosphorylation of STAT3, a hallmark of MDSC) [32]. Peroxynitrite is an anion derived from the reaction of •NO with •O2−, Figure 1. Figure 1. Reaction between the radical •NO and superoxide anion •O2−, yielding peroxynitrite. Peroxynitrite is unstable and breaks down into •NO2 and •OH. •NO2 reacts with the tyrosine residues of key immune cell signaling proteins and inactivates them by nitration. Figure 1. Reaction between the radical •NO and superoxide anion •O2−, yielding peroxynitrite. Peroxynitrite is unstable and breaks down into • NO 2 and • OH. • NO 2 reacts with the tyrosine residues of key immune cell signaling proteins and inactivates them by nitration. Nitration alters the TcR and MHC (major histocompatibility complex) on antigen-presenting cells, which prevents T cells from recognizing antigens [ 36 ]. Therefore, targeting MDSCs with peroxynitrite inhibitors is a therapeutic pathway to improve the response to immunotherapy [ 37 ]. The two MDSC subsets use different mechanisms to suppress T-cell proliferation. The PMN-MDSC expresses high levels of ROS and low levels of • NO, and Vaccines 2023,11, 218 4 of 22 the M-MDSC expresses low levels of ROS and high levels of • NO. Arginase 1 expression is common to both [ 38 ] and suppresses antigen-specific T-cell proliferation to an equal extent despite having different mechanisms of action [39]. 3. Role of Myeloid-Derived Suppressor Cells in Cancer In the early 1970s, initial research was published linking tumor growth to the proliferation of immunosuppressive myeloid cells. Research conducted in the 1980s and 1990s by Diana Lopez, Jim Talmadge, M. Rita Young, and Hans Schreiber showed that different types of myeloid cells suppressed immunological function in tumor cell growth [3]. In most types of cancer, PMN-MDSCs account for more than 80% of MDSCs. There is another small group (less than 3%) of cells with myeloid colony-forming activity that represent a mixture of myeloid progenitors and precursors [40]. Myeloid-derived suppressor cells are present in virtually all cancer patients, impair adaptive and innate anti-tumor immunity, and promote tumor progression by non-immune mechanisms. Their widespread presence combined with their diverse peritumoral activities makes them a major obstacle to cancer immunotherapy [ 41 ]. MDSCs have been detected in cancer patients and mice with tumors for more than 30 years. They inhibit antitumor immunity and act through CBI-independent signaling pathways [ 42 , 43 ]. In addition, MDSCs interfere with antibody treatments and promote tumor development via a variety of non-immune pathways [44]. Tumor immunity represents a new avenue for improved cancer therapy. Evasion of the immune system is a key feature of tumors [ 45 ]. To successfully establish themselves in a host and continue to grow, tumor cells use biochemical signals to hide from the host’s immune response and remain undetected. Immunotherapy aims to restore the immune response and immunity to cancer and has revolutionized cancer therapy in recent years. However, immunosuppressive rogue cells such as tumor-associated macrophages TAM, tumor-associated neutrophils TAN, regulatory T cells Treg, regulatory dendritic cells RegDC, cancer-associated fibroblasts, and MDSCs remain a major obstacle to immunotherapy and contribute to treatment failure, reduced life expectancy, and poor prognosis [ 46 – 48 ]. Checkpoint blockade immunotherapy CBI has been a revolution in cancer treatment because the patient’s adaptive immune system can eradicate malignant cells once the immunosuppressive mechanisms are neutralized [ 43 ]. Immune checkpoint inhibitors have successfully improved outcomes in various tumor types, and immune cell-based therapy is also gaining attention [ 49 ]. However, this IBC treatment is only effective in a certain group of cancer patients, as other immunosuppressive mechanisms appear to block T-cell-induced anti-tumor immunity [50]. As seen, immunosuppression plays a crucial role in tumor progression and contributes to the frequent failure of immunotherapy treatments and potential cancer vaccines, so it is necessary to address the study of the inhibition of these MDSCs to ensure the viability of the cancer immunotherapy approach. Elimination of suppressor factors is now recognized as a necessary step toward effective cancer immunotherapy. Drugs such as gemcitabine can be used to completely remove MDSCs from the body. There was no appreciable decrease in the number of B and T cells, suggesting that this effect occurs only in MDSCs. In contrast, a study of 17 patients with early-stage breast cancer found that chemotherapy with doxorubicin and cyclophosphamide resulted in an increase in the number of MDSCs in the peripheral blood [51]. 4. Role of Myeloid-Derived Suppressor Cells in COVID-19 MDSCs have been described in a number of viral diseases, including respiratory infections [ 52 ]. It is still unclear how these cells contribute to the development of infectious diseases. On the one hand, MDSCs hinder the body’s ability to eliminate pathogens from the bloodstream and from the site of infection by suppressing the actions of effector-immune cells. On the other hand, MDSCs can prevent host organs from suffering lethal dysfunction by limiting the hyperinflammation and “cytokine storm” caused by infection [53]. Vaccines 2023,11, 218 5 of 22 During the infective process of COVD-19, pathogen-associated molecular patterns PAMPs from the replication of SARS-CoV-2 in host cells are recognized by a variety of membrane PRR pattern recognition receptors, including Toll-like receptors TLR-3, -4, -7, and -8; in addition to the porin domain of the NOD-like receptor family NLRP3, the retinoic acid-inducible RIG1, melanoma differentiation-associated protein 5 MDA5, and LGP2 are also present. Single-stranded RNA of SARS-CoV-2 is recognized by TLR-7 and -8, while double-stranded RNA intermediates are bound to TLR -3, RIG1, LGP2, and MDA5. SARS-CoV-2 proteins are recognized by TLR-4 and NLRP3 [54–56]. Moreover, viral replication triggers the synthesis of host-specific threat-associated molecular patterns DAMPs, which are then secreted extracellularly by injured or dying infected cells after rupture of the plasma membrane and recognized by cells bearing pattern recognition receptors PRRs. Calprotectin S100A8/A9, HMGB1 protein, mitochondrial DNA mt-DNA, and extracellular secreted nicotinamide phosphoribosyl transferase eNAMPT are important DAMPs associated with COVID-19 [ 57 – 59 ]. In response to PAMPs and DAMPs, many cell types secrete inflammatory mediators, chemokines, and growth factors such as interleukins IL-1B, IL-6, IFN α / β , TNFα , chemokine ligand CXCL8/IL-8, CXCL10, chemokine ligand CCL5, granulocyte colony-stimulating factors G-CSF, and granulocytemacrophage GM-CSF [60,61]. Recent studies point to a link between tissue damage and inflammation, in which the damage-associated molecular patterns of DAMPs play a key role in the etiology of severe COVID-19 [ 62 ]. NETs (neutrophil extracellular traps) are involved in the pathogenesis of COVID-19 and this can be seen in the fact that treatment of healthy neutrophils with serum from COVID-19 patients triggers NET release; and, in general, SARS-CoV-2 stimulates neutrophils to release NETs [ 63 ]. Several components of NETs, together with factors such as oxidative stress, contribute to the release of endogenous DAMPs, leading to severe hypoxia and ultimately acute respiratory distress syndrome ARDS in patients with severe COVID-19 [64]. The innate immune sets the adaptive response, which begins its activation within days [ 65 ]. Antigen-specific B cells, CD4+ T helper cells, and CD8+ cytotoxic T cells work together to orchestrate the adaptive response. However, CD4+ T helper cells are more prevalent than CD8+ cytotoxic T cells in SARS-CoV-2 [ 66 ] The sequencing of the immune response implies that innate immunity is activated first, followed by adaptive immunity, acting synchronously to eliminate the virus and damaged cells [ 67 , 68 ]. After the pathogen is eliminated, a series of immunoregulatory cell populations terminate the inflammatory response and restore tissue homeostasis. There is a multifactorial risk that can affect the course of COVID-19 disease, including hypertension, cancer, diabetes, as well as respiratory, cerebrovascular, and chronic kidney diseases [ 69 ]. These comorbidities are associated with an immunocompromised state characterized by an impaired immune response and decreased ability to fight viruses, as well as advanced age [70,71]. Myeloid cells play an important role in the pathogenesis of SARS-CoV-2, as evidenced by the frequent observation of a huge expansion of the myeloid-cell compartment and a decrease in the leukocyte compartment [ 72 , 73 ]. In COVID-19, myeloid cells are characterized by decreased antigen presentation and increased immunosuppressive characteristics, both of which are consistent with the profile of MDSC [ 73 ]. M2 macrophages, regulatory dendritic cells, regulatory T cells, and myeloid-derived suppressor cells are the primary immunoregulatory cell subsets that contribute to the attenuation of inflammation [53,74–76]. Although MDSCs can suppress a range of immune cells (including NK and B cells), their main goal is to induce T-cell immunosuppression. Therefore, evaluating their ability to block immune effector-cell activity is a critical component of understanding MDSCs [ 53 , 77 , 78 ]. In patients with COVID-19, MDSCs have been studied both in the peripheral blood and, more specifically, in the airways. As noted by Dean et al. 2021, large numbers of Arg1expressing PMN-MDSCs were found in the lungs of COVID-19-deceased patients. This finding suggests that SARS-CoV-2 infection begins in the upper airways but progresses to the lower airways, where local recruitment of MDSCs is observed [ 79 ]. L-arginine is Vaccines 2023,11, 218 6 of 22 converted to ornithine via the enzyme arginase 1 Arg1, which inhibits T-cell proliferation and causes significant molecular changes in T cells, such as low CD3 ζ chain expression and reduced IFNγ production [ 80 ]. Interleukin IL -10 and transforming growth factor TGFβ produced by MDSCs inhibit T-cell activation and recruit regulatory Treg cells, respectively [ 81 ]. In addition, MDSCs can bind to PD1 molecules on T cells via their ligand PDL1 and induce T-cell death via cell-to-cell interactions [82]. PMN-MDSC generate ROS and nitric oxide • NO, and this allows the formation of peroxynitrite, which in turn is broken down to generate two new radicals, • NO 2 and • OH, with a high oxidative capacity [ 83 ]. • NO 2 induces T-cell receptor nitration on CD8+ cells (they are cytotoxic, like CD4+ T-helper cells, and express the TCR-cell receptor), during cell-to-cell contacts [ 84 ]. This nitration causes T cells to lose their ability to bind to the phosphorylated MHC (major histocompatibility complex) and therefore are unable to perform their function and respond to specific antigens, resulting in antigen-specific T cell tolerance [85]. Finally, according to a number of studies, there is a correlation between the number of MDSCs and the severity of COVID-19. Patients who required treatment in the ICU had more PMN-MDSCs than patients who did not, according to a 2020 study by Sacchi et al. [ 86 ]. In addition, Reizine et al. 2021 discovered that patients with acute respiratory distress syndrome ARDS have more PMN-MDSCs and M-MDSCs than individuals with moderate disease [87]. 5. Reactive Oxygen Species and Its Generation In cell chemistry, reactive oxygen species ROS are highly reactive species formed from the diatomic oxygen O 2 , examples of ROS being superoxide anion, hydrogen peroxide, hydroxyl radical, singlet oxygen, and alpha oxygen. In a biological and molecular context, ROS species are by-products of normal oxygen metabolism and play an important role in cell signaling and homeostasis, and on a physiological level they are intrinsic to cellular functioning (at low and stationary levels in normal cells [88]). Chemically, the • O 2− anion is a by-product of the respiration chain in the innermitochondrial membrane [ 89 ], shown in Figure 2. As a necessary condition in processes such as chemical reactions, the Gibbs free energy determines how much work a thermodynamically closed system can do at a given temperature and pressure. Since the Gibbs energy for the sequential reduction of O 2 with H + and e − is negative Figure 2, the reaction proceeds spontaneously (∆Go ≤0) [90]. Vaccines 2023, 11, 218 7 of 24 suppressor cells are the primary immunoregulatory cell subsets that contribute to the attenuation of inflammation [53,74–76]. Although MDSCs can suppress a range of immune cells (including NK and B cells), their main goal is to induce T-cell immunosuppression. Therefore, evaluating their ability to block immune effector-cell activity is a critical component of understanding MDSCs [53,77,78]. In patients with COVID-19, MDSCs have been studied both in the peripheral blood and, more specifically, in the airways. As noted by Dean et al. 2021, large numbers of Arg1-expressing PMN-MDSCs were found in the lungs of COVID-19-deceased patients. This finding suggests that SARS-CoV-2 infection begins in the upper airways but progresses to the lower airways, where local recruitment of MDSCs is observed [79]. Larginine is converted to ornithine via the enzyme arginase 1 Arg1, which inhibits T-cell proliferation and causes significant molecular changes in T cells, such as low CD3ζ chain expression and reduced IFN-γ production [80]. Interleukin IL -10 and transforming growth factor TGF-β produced by MDSCs inhibit T-cell activation and recruit regulatory Treg cells, respectively [81]. In addition, MDSCs can bind to PD1 molecules on T cells via their ligand PDL1 and induce T-cell death via cell-to-cell interactions [82]. PMN-MDSC generate ROS and nitric oxide • NO, and this allows the formation of peroxynitrite, which in turn is broken down to generate two new radicals, • NO 2 and • OH, with a high oxidative capacity [83]. • NO 2 induces T-cell receptor nitration on CD8+ cells (they are cytotoxic, like CD4+ T-helper cells, and express the TCR-cell receptor), during cell-to-cell contacts [84]. This nitration causes T cells to lose their ability to bind to the phosphorylated MHC (major histocompatibility complex) and therefore are unable to perform their function and respond to specific antigens, resulting in antigen-specific T cell tolerance [85]. Finally, according to a number of studies, there is a correlation between the number of MDSCs and the severity of COVID-19. Patients who required treatment in the ICU had more PMN-MDSCs than patients who did not, according to a 2020 study by Sacchi et al. [86]. In addition, Reizine et al. 2021 discovered that patients with acute respiratory distress syndrome ARDS have more PMN-MDSCs and M-MDSCs than individuals with moderate disease [87]. 5. Reactive Oxygen Species and Its Generation In cell chemistry, reactive oxygen species ROS are highly reactive species formed from the diatomic oxygen O 2 , examples of ROS being superoxide anion, hydrogen peroxide, hydroxyl radical, singlet oxygen, and alpha oxygen. In a biological and molecular context, ROS species are by-products of normal oxygen metabolism and play an important role in cell signaling and homeostasis, and on a physiological level they are intrinsic to cellular functioning (at low and stationary levels in normal cells [88]). Chemically, the • O 2− anion is a by-product of the respiration chain in the innermitochondrial membrane [89], shown in Figure 2. As a necessary condition in processes such as chemical reactions, the Gibbs free energy determines how much work a thermodynamically closed system can do at a given temperature and pressure. Since the Gibbs energy for the sequential reduction of O 2 with H + and e — is negative Figure 2, the reaction proceeds spontaneously (∆Go ≤ 0) [90]. Figure 2. O 2 reduction chain to • O 2− , H 2 O 2 and H 2 O. In the next ROS step, • O 2− is converted to hydrogen peroxide (H 2 O 2 ) by the superoxide dismutase family of enzymes [91], and in the presence of the enzyme Figure 2. O2reduction chain to •O2−, H2O2and H2O. In the next ROS step, • O 2− is converted to hydrogen peroxide (H 2 O 2 ) by the superoxide dismutase family of enzymes [ 91 ], and in the presence of the enzyme myeloperoxidase MPO and chloride ion, generates hypochlorous acid HOCl [ 92 ], a potent antibacterial agent that is part of the innate immune system’s antimicrobial arsenal. Other potent oxidants involved are peroxynitrite ONOO − (formed by the reaction between the superoxide anion and the nitric oxide • NO) and hydroxyl radical ( • OH, formed by the Fenton or Haber–Weiss reaction or by the decomposition of ONOO−,•NO2and •OH). In antimicrobial responses, mitochondrial and NOX enzymes are the most important and best-studied ROS generators in macrophages. However, macrophages have other ROS sources. The oxidation of hypoxanthine and xanthine to uric acid is catalyzed by the enzyme xanthine oxidase (XO), which degrades xanthine and is predominantly localized in the cytosol, where it plays a crucial role in purine nucleotide catabolism [ 93 ]. Hydrogen peroxide is generated as a by-product during oxidation. XO has important physiological Vaccines 2023,11, 218 7 of 22 functions; a few studies have examined its activity in macrophages and suggest that it may be involved in inflammasome activation and cytokine expression [94]. NADPH oxidase, the enzyme complex known as NOX (nicotinamide adenine dinucleotide phosphate oxidase), is bound to the cell membrane in the extracellular space and is also found in the membranes of phagosomes used by neutrophils to engulf bacteria [ 95 ]. Human isoforms of the catalytic enzyme complex include NOX1–5 and DUOX1–2. The first mammalian NOX to be discovered was NOX2, the phagocyte NADPH oxidase [ 96 ]. NOX1 is extensively expressed in different cells, particularly in colonic epithelial cells [ 97 ] and NOX2 is expressed mostly in phagocytes, with lower manifestation in vascular smoothmuscle cells and human endothelial cells [98,99]. NOX catalyzes the production of a superoxide free radical by transferring one electron to oxygen from NADPH. Neutrophilic NOX produces • O 2− almost instantaneously, whereas the vascular enzyme produces • O 2− in minutes to hours, and in this case the radical anion appears to be released mainly intracellularly. In humans, a lack of ROS triggers chronic bacterial infections, while its uncontrolled release causes pathologies due to excessive inflammation [ 100 ]. Professional phagocytes such as neutrophils (polymorphonuclear neutrophils PMNs), eosinophils, monocytes, and macrophages use superoxide-generating NADPH oxidase NOX as part of their arsenal of antimicrobial pathways to generate high levels of ROS [ 101 ]. To generate superoxide, NADPH oxidase transfers an electron from NADPH to an oxygen molecule [102]. Peroxisomes are organelles found in the cytoplasm of almost all eukaryotic cells. Superoxide and hydrogen peroxide are byproducts of fatty-acid oxidation. Because peroxisomes can rapidly generate and scavenge H 2 O 2 and • O 2− , they play a key role in controlling the ebb and flow of reactive oxygen species ROS. Cyclooxygenases and Lipoxygenases; both families of COX and LOX generate ROS as a by-product, in the arachidonic acid AA-metabolizing process. All three types of life forms, bacteria, archaea, and eukaryotes, have heme monooxygenases called cytochrome P450 CYP enzymes. These enzymes play an important role in the metabolism of sterols, fatty acids, eicosanoids, and vitamins, as well as in the detoxification of drugs and xenobiotics [ 103 – 105 ]. Chemical and enzymatic reactions generating superoxide •O2−are shown in Figure 3. Vaccines 2023, 11, x FOR PEER REVIEW 8 of 22 Figure 3. Chemical and enzymatic reactions generation of ROS. Reduction of O2 produces •O2−, it is the precursor for all other ROS subspecies. Rapid dismutation of superoxide to peroxide allows its further conversion to OCl by myeloperoxidase MPO [92] or by Fe3+ to •OOR or •OH. The Fenton reaction, in which peroxide is oxidized by Fe3+ with •OH as a reactive intermediate, rarely occurs in cells. O2 is rarely excited to 1O2 by radiation in mammals. ROS can be divided into two families: (i) reactive free radicals, being the first formed by the superoxide anion •O2−, the hydroxyl •OH, the alkoxyl •OOR and peroxyl •OOH radicals [106]; and (ii) the non-radical species hydrogen peroxide H2O2 [91], singlet oxygen 1O2 [107], and ozone O3 [108]. The radical •O2− quickly dismutates to peroxide, either spontaneously in the presence of water or catalyzed by superoxide dismutase, SOD1, SOD2, and SOD3 [109]. Species •O2− and H2O2 are the two most abundant ROS species in cells, the first being more reactive than the second. Superoxide can only pass through cell membranes via ion channels, such as voltage-dependent anion channels VDACs [110] unlike H2O2, which is more freely diffusible [111]. An increase in •O2− levels is associated with oxidative stress and cellular damage because it can react with lipids, proteins, and DNA [83]. 6. Role of Reactive Species on Innate and Adaptive Immunity The immune system includes cells, organs, proteins, and tissues throughout the body and consists of components such as leukocytes, spleen, bone marrow, lymphatic system, thymus, tonsils, adenoids, and appendix. There are three types of immunity in humans: innate, adaptive, and passive. While innate immunity and acquired immunity were once thought to be unrelated, recent research has shown that the two are in fact closely intertwined [112]. All multicellular organisms have an innate immune system, a rudimentary defense mechanism that relies on macrophages, neutrophils, the complement system, natural killer cells, gamma delta T lymphocytes, and dendritic cells to function [113]. Figure 4 is an illustration of the immune system. Figure 3. Chemical and enzymatic reactions generation of ROS. Reduction of O 2 produces • O 2− , it is the precursor for all other ROS subspecies. Rapid dismutation of superoxide to peroxide allows its further conversion to OCl by myeloperoxidase MPO [ 92 ] or by Fe 3+ to • OOR or • OH. The Fenton reaction, in which peroxide is oxidized by Fe 3+ with • OH as a reactive intermediate, rarely occurs in cells. O2is rarely excited to 1O2by radiation in mammals. ROS can be divided into two families: (i) reactive free radicals, being the first formed by the superoxide anion • O 2− , the hydroxyl • OH, the alkoxyl • OOR and peroxyl • OOH radicals [ 106 ]; and (ii) the non-radical species hydrogen peroxide H 2 O 2 [ 91 ], singlet oxygen 1 O 2 [ 107 ], and ozone O 3 [ 108 ]. The radical • O 2− quickly dismutates to peroxide, either spontaneously in the presence of water or catalyzed by superoxide dismutase, SOD1, Vaccines 2023,11, 218 8 of 22 SOD2, and SOD3 [ 109 ]. Species • O 2− and H 2 O 2 are the two most abundant ROS species in cells, the first being more reactive than the second. Superoxide can only pass through cell membranes via ion channels, such as voltage-dependent anion channels VDACs [ 110 ] unlike H 2 O 2 , which is more freely diffusible [ 111 ]. An increase in • O 2− levels is associated with oxidative stress and cellular damage because it can react with lipids, proteins, and DNA [83]. 6. Role of Reactive Species on Innate and Adaptive Immunity The immune system includes cells, organs, proteins, and tissues throughout the body and consists of components such as leukocytes, spleen, bone marrow, lymphatic system, thymus, tonsils, adenoids, and appendix. There are three types of immunity in humans: innate, adaptive, and passive. While innate immunity and acquired immunity were once thought to be unrelated, recent research has shown that the two are in fact closely intertwined [ 112 ]. All multicellular organisms have an innate immune system, a rudimentary defense mechanism that relies on macrophages, neutrophils, the complement system, natural killer cells, gamma delta T lymphocytes, and dendritic cells to function [ 113 ]. Figure 4is an illustration of the immune system. Vaccines 2023, 11, x FOR PEER REVIEW 9 of 22 Figure 4. Mechanisms of the immune system, both innate and adaptive. As the name suggests, innate immunity is something that every person is born with, and it immediately protects the body from some pathogens. The skin and the mucous membranes of the throat and intestines are part of this innate immunity, which serves as the first line of protection against infectious agents. All plants, fungi, mammals, and even the earliest multicellular organisms have innate immunity, a form of nonspecific immunity that has evolved over millions of years. Immune responses to pathogens are complicated by ROS in innate immunological processes such as the respiratory burst and inflammasome activation. During a respiratory burst, many cell types rapidly release oxygen and hydrogen peroxide. Phagocytic macrophages and neutrophils are myeloid cells that play a key role in the respiratory burst, which is necessary for the subsequent destruction of bacteria or other pathogens that have been internalized. For a respiratory burst to occur, NADPH oxidase activity must be increased by a factor between 10–20, which increases oxygen demand [114]. Peroxynitrite levels increase when •NO and •O2− are present; these levels contribute to the “cauldron effect” when the environment is acidic. Pathogen lysis is facilitated by this mechanism, which is activated during phagocytosis due to the acidic environment of the phagosomes [115]. The so-called “cauldron effect” in the phagosome provides the cell Figure 4. Mechanisms of the immune system, both innate and adaptive. Vaccines 2023,11, 218 9 of 22 As the name suggests, innate immunity is something that every person is born with, and it immediately protects the body from some pathogens. The skin and the mucous membranes of the throat and intestines are part of this innate immunity, which serves as the first line of protection against infectious agents. All plants, fungi, mammals, and even the earliest multicellular organisms have innate immunity, a form of nonspecific immunity that has evolved over millions of years. Immune responses to pathogens are complicated by ROS in innate immunological processes such as the respiratory burst and inflammasome activation. During a respiratory burst, many cell types rapidly release oxygen and hydrogen peroxide. Phagocytic macrophages and neutrophils are myeloid cells that play a key role in the respiratory burst, which is necessary for the subsequent destruction of bacteria or other pathogens that have been internalized. For a respiratory burst to occur, NADPH oxidase activity must be increased by a factor between 10–20, which increases oxygen demand [114]. Peroxynitrite levels increase when • NO and • O 2− are present; these levels contribute to the “cauldron effect” when the environment is acidic. Pathogen lysis is facilitated by this mechanism, which is activated during phagocytosis due to the acidic environment of the phagosomes [ 115 ]. The so-called “cauldron effect” in the phagosome provides the cell with an isolated environment in which it can carry out the destruction of foreign bodies. Here ROS, • NO, and RNS work together to trigger redox [ 116 ]. Superoxide • O 2− is generated on the membranes of the endosome of the phagocytosing cells, with the involvement of NADPH oxidase NOX [117]. Nitric oxide • NO is a cellular signaling molecule, found in vascular endothelium cells, platelets, macrophages, and neuronal cells. • NO suppresses platelet aggregation, limits endothelial adhesion of neutrophils, defines basal vascular tone, and modulates myocardial tone. To maintain steady vascular tone, vascular endothelial cells secrete a steady stream of • NO. The guanidine nitrogen atoms of L-terminal arginine are oxidized, producing •NO [117]. With a half-life of only about 10 −2 s, peroxynitrite ONOO − is a potent oxidant with a short half-life. Lipid peroxidation, inactivation of enzymes and proteins, and mitochondrial dysfunction are just some of the effects of its derivatives. In cells such as macrophages, ONOO − is critical for the destruction of invading pathogens [ 118 ]. Inadequate control of its production has been associated with increased risk of cardiovascular disease, neurological disorders, and cancer. The byproducts of peroxynitrite degradation are • NO 2 , • OH, and •CO3−[119]. Myeloperoxidase MPO, a hydrogen peroxide oxidoreductase, is found in macrophages as well as various other cell types, fluids (saliva, synovial fluid, and semen), and tissues (heart, kidney, skin, liver, and placenta) [ 92 ]. Most of the enzyme originates from neutrophils, where it is found in lysosomes [ 120 ]. MPO catalyzes the oxidation of Cl − anion using H 2 O 2 to produce HOCl, a highly reactive chlorinating and oxidizing agent and the primary strong oxidant produced in significant amounts by neutrophils [121]. Lymphocytes perform adaptive immunity by remembering the appearance of foreign substances and building a new immune response to protect the body from future infections. Certain immune cells and antibodies are required for adaptive immunity. T and B cells play a central role in the adaptive immune response, which aims to eradicate infections and create an immunological memory [122]. Uniquely, vertebrates have adaptive immunity, so they can recognize and destroy specific pathogens. This immune response can identify and remember pathogens, generating increasingly potent consecutive responses to the re-encountered pathogen. 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