Myeloid-Derived Suppressor Cells in Cancer and COVID-19

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1		José Pérez de la Lastra	--	2953	2023-02-01 10:36:51	\|
2	format	Jason Zhu	Meta information modification	2953	2023-02-02 03:13:20	\|

This entry is adapted from the peer-reviewed paper 10.3390/vaccines11020218

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.

myeloid-derived suppressor cells cancer COVID-19

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 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].

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]^[5]^[6]^[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-1β, PGE2, TNF-α, and VEGF and by transcriptional regulators including STAT3, CEBP/β, STAT5, IRF8, S100A8/9, RB, TIPE2, and GCN2 ^[4]^[5]^[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, 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]^[32]^[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 p47^phox 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, p47^phox 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. 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 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]^[47]^[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].

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]^[55]^[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]^[58]^[59]. In response to PAMPs and DAMPs, many cell types secrete inflammatory mediators, chemokines, and growth factors such as interleukins IL-1B, IL-6, IFNα/β, TNF-α, chemokine ligand CXCL8/IL-8, CXCL10, chemokine ligand CCL5, granulocyte colony-stimulating factors G-CSF, and granulocyte-macrophage 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]^[75]^[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]. L-arginine 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, ^•NO₂ and ^•OH, with a high oxidative capacity ^[83]. ^•NO₂ 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].

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Celia María Curieses Andrés

José Manuel Pérez de la Lastra

Celia Andrés Juan

Francisco J. Plou

Eduardo Pérez-Lebeña

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Update Date: 02 Feb 2023

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