Immunomodulatory actions of myeloid-derived suppressor cells in the context of innate immunity

Myeloid cells

The complex association between MDSCs and macrophages is reflected by a wide network of interactions. M2 macrophages have immunosuppressive and pro-tumour characteristics and are the most abundant type in the population of the tumour-associated macrophages (TAMs). ²² Their crosstalk leads to decreased expression of IL6, IL12, and major histocompatibility complex II (MHCII) by macrophages, as well as increased production of IL10 by MDSCs, as proposed from the studies by Beury et al., Bunt et al., and Sinha et al. The net result of this two-way interaction is the polarisation towards the M2 type of macrophages.^23–25 Furthermore, M2 macrophages secrete substances in the TME that can induce the production of MDSCs, whereas MDSCs can develop to M2 macrophages themselves under specific triggers.^15,18,26 Kwak et al., for example, proposed that M-MDSCs transform to immunosuppressive macrophages under the influence of S100A9. ²⁷

Although MDSCs appear to hinder the function of dendritic cells (DCs), the ways that these cells crosstalk is yet not clear. ¹⁵ Hu et al. showed in their hepatocellular carcinoma (HCC) mouse model that the production of IL10 by MDSCs inhibited the secretion of IL12 by DCs affecting, thus, their actions. More specifically the authors evaluated the TLR-induced production of IL12 by DCs and the T-cell stimulatory activity of DCs in HCC mice and both were found decreased. ²⁸ The functions of DCs, i.e., their maturation, their capacity to take up antigens, their migration ability and their capacity to induce the production of interferon γ (IFN-γ) by T cells, were also impaired by M-MDSCs in the study of Poschke et al. ²⁹

In several studies, MDSCs were shown to directly interact in a cell contact-dependent manner with mast cells (MCs). ³⁰ Danelli et al. and Jachetti et al. described that MCs enhanced the immunosuppressive activity of PMN-MDSCs through the CD40-CD40 ligand (CD40L) interaction.^31,32 Saleem et al. showed that the co-culture of MDSCs and MCs resulted in increased levels of IL6, IL13, tumour necrosis factor α (TNF-α), and macrophage inflammatory protein 1α (MIP1α), and that MCs enhanced the pro-tumour effects of M-MDSCs but also the antimicrobial effects of PMN-MDSCs. ³³ Martin et al. proposed that the histamine released by MCs positively influences the recruitment of MDSCs, and thus allergic patients present with higher counts of these cells. ³⁴

Lymphoid cells

MDSCs also interact with natural killer (NK) cells and hamper their cytotoxicity.^16,35,36 They produce several mediators that inhibit the functionality of NK cells, such as transforming growth factor β (TGF-β), according to the studies of Li et al. and Mao et al.^37,38 Stiff et al. further showed that NO produced by MDSCs impairs NK cytotoxicity through hindering their Fc receptor (FcR)-mediated actions. ³⁹ Liu et al. performed experiments with tumour-bearing mice, where MDSCs appeared to inhibit NK cytotoxicity via reduced expression of signal transducer and activator of transcription 5 (STAT5) and reduced production of perforin. ⁴⁰ As described before, MDSCs produce indoleamine 2,3 dioxygenase (IDO1), and Zhang et al. proposed the axis IDO1/miR-18a/NKG2D/NKG2DL for the MDSC-induced NK-cell suppression. NKG2D is a conserved receptor on NK cells and NKG2DL its ligand. Both molecules are downregulated by miR-18a. The increase of IDO1 expression was correlated with decreased expression of NKG2D and NKG2DL and decreased NK cytotoxicity, which, according to the authors, would lead to decreased capability of NK cells to kill tumour cells. NK-cell cytotoxicity was studied by Zhang et al. in co-cultures with EMT6 cells. ⁴¹ Rieber et al. also studied the effect of MDSCs on the NK-cell cytotoxicity. More specifically, cord blood PMN-MDSCs were incubated with NK cells. Afterwards, NK cells were incubated with K562 tumour cells, and the authors concluded that MDSCs impair the NK-cell cytotoxicity in a contact-dependent manner. ⁴²

Innate lymphoid cells (ILC) are distinct types of lymphocytes, separated in three major subpopulations, i.e., ILC1, ILC2, and ILC3. They are tissue-resident and are thought to be the analog of T cells in the innate immunity system, as they do not express the specified antigen repertoire of T cells. ILC1 is the analog of Th1 cell acting against intracellular pathogens, ILC2 is the analog of Th2 cell acting against large extracellular pathogens, such as parasites, and ILC3 is the analog of Th17 cell acting against smaller extracellular pathogens, such as bacteria. NK cells and lymphoid tissue-inducer (LTi) cells (present during embryogenesis) are also characterised as ILCs by some researchers.^30,43 Tumino et al. reviewed the interaction between MDSCs and ILCs in the TME. However, there is still a lack of original research directly studying how MDSCs affect ILC populations. Tumino et al. suggested that since ILC1 resemble NK cells, these cells may be affected by MDSCs in the same way. Also, the authors suggested that the production of TGF-β by MDSCs inhibits the transformation of ILC1 to NK cells ⁴⁴ Chevalier et al. suggested that ILC2 induce M-MDSC recruitment and actions via production of IL13 in the context of bladder cancer. ⁴⁵ Tumino et al. also suggested that ILC3 that are tumour-promoting cells may induce MDSCs via the production of IL17 and IL10, ⁴⁴ although this is based on original research concerning ILCs and not directly MDSCs. ⁴⁶

Gammadelta T (γδT17) cells is another immune cell population that shares characteristics of both innate and adaptive immune cells. These cells are the major producers of IL17. Yan et al. described a correlation between γδT17 and MDSC counts in colorectal cancer and also showed that γδT17 cells enhance the recruitment of MDSCs by producing IL17. ⁴⁷ Rani et al. showed via experiments in mice that γδT17 cells were important for the increase of MDSCs in the burn wound and thus facilitated the wound healing. ⁴⁸

It is worth noting that MDSCs mainly display a suppressive effect on T- and B-cell actions. Specifically, MDSCs lead to the depletion of essential amino acids for cell survival, homing and proliferation, impair T-cell receptor function, increase the apoptosis of T and B cells, and induce the development of T regulatory cells. ¹⁶ However, as these cells are part of the adaptive immunity system, we chose not to review here in detail the interaction between MDSCs and these cell populations.

Negative impact in infection

There are a number of studies showing that MDSCs worsen the infections by Staphylococcus aureus. Tebartz et al. showed with in vitro and in vivo experiments the correlation of the expansion of both MDSC subclasses with acute exacerbation and chronic infection by Staphylococcus aureus in mice. ⁵² Heim et al. and Thurlow et al. investigated how MDSCs affect the course of the orthopaedic biofilm infection by Staphylococcus aureus. Interestingly, according to the authors, MDSCs are the main cell population that infiltrates the biofilm. These cells are recruited by IL12 and obstruct the host defense with their immunosuppressive functionality, i.e., via arginase-1 (Arg-1) and inducible NO synthase (iNOS) activity, reactive oxygen species (ROS) production, and secretion of IL10, leading to attenuated activity of macrophages and monocytes of the host.^53–55 According to Skabytska et al., MDSCs impair the host response in skin infections by Staphylococcus aureus. ⁵⁶ Furthermore, their increased populations in the lung and peripheral blood unfavourably influence the course of the infection by Mycobacterium tuberculosis.^57–62 Rieber et al. suggested that Pseudomonas aeruginosa induces MDSCs via flagellin, which acts as a pathogen-associated molecular pattern (PAMP). ⁶³ Interestingly, Everett et al. studied the pathogenic capacity of Pseudomonas aeruginosa in burn wounds. Low arginine levels, which were correlated with the counts of MDSCs, as these cells produce Arg-1, seem to be related with increased virulence of the microbe. ⁶⁴

Other non-bacterial pathogens, such as viruses, may also induce MDSCs. For example, Cai et al. showed that hepatitis C virus (HCV) RNA load in patients with chronic hepatitis C is correlated with the counts of MDSCs. ⁶⁵ Qin et al. showed that patients with chronic infection by human immunodeficiency virus-1 (HIV-1) had increased counts of M-MDSCs, which take part in the decreased T-cell response. ⁶⁶ Interestingly, MDSCs have already been studied in infection by SARS-CoV-2 by Agrati et al., showing that patients with severe coronavirus disease (COVID-19) display higher counts of MDSCs than milder cases. ⁶⁷ Falck-Jones et al. also studied MDSCs in COVID-19 patients. M-MDSCs were found increased in the blood, but not the airways, of the patients and were correlated with the disease severity. ⁶⁸

Positive impact in infection

Despite the traditional view concerning the negative role of MDSCs in infectious diseases, several recent studies have argued for their favourable roles against particular pathogens. For instance, Candida albicans and Aspergillus fumigatus induce MDSCs via dectin-1. Both pathogens lead to the induction of immunosuppressive PMN-MDSCs, but only in the case of Candida albicans, adoptive transfer of MDSCs is associated with better survival of the mice. ⁶⁹ Saleem et al. showed that PMN-MDSCs contributed to the resolution of infection by Nippostrongylus brasiliensis in their mouse model. ³³

In lower respiratory tract infections by Klebsiella pneumoniae, according to Poe et al., MDSCs are beneficial for the recovery of the host, as they facilitate the clearance of the apoptotic neutrophils via the secretion of IL10. ⁷⁰ As reviewed previously, MDSCs are particularly crucial for the feto-maternal tolerance, and they are present in large numbers during pregnancy as well as post-partum in the neonatal and infantile periods. ¹⁰ Abnormalities in their number or functionality are related to poor clinical outcomes. Leiber et al. compared PMN-MDSCs and neutrophils in neonates. Interestingly, they showed that neonatal PMN-MDSCs not only maintained their immunosuppressive character, but also had antibacterial properties. These cells were capable of suppressing T-cell activity, while also phagocytosing Gram-negative, such as Escherichia coli, and Gram-positive, such as Streptococcus pneumoniae, bacteria. Despite the differences in cytokine secretion and apoptosis between PMN-MDSCs and neutrophils, their phagocytic activity was similar. ⁸ He et al. studied in vitro MDSCs from both newborn humans and mice using RNA-sequencing, revealing an enriched antimicrobial response network in both subtypes, i.e., potent capability of killing Escherichia coli in M-MDSCs and Escherichia coli and Candida albicans in PMN-MDSCs. ⁷¹

The way that MDSCs exert their possible antibacterial properties is poorly studied. However, since PMN-MDSCs resemble mature neutrophils, as far as their morphology and markers are concerned, we could assume that PMN-MDSCs may act in a similar way against pathogens. Intracellular granules have antimicrobial proteins that can kill a phagocytosed pathogen after their junction with the phagosome or an extracellular pathogen after their release. Phagocytosed pathogens can also be killed by the release of ROS and hydrolytic enzymes in the phagosome. MDSCs do have this panoply, and it is thus possible to act in this way against pathogens. ⁷²

Impact of MDSCs in sepsis

Sepsis is characterised in the early stages by an initial proinflammatory response and in the late stages by immunosuppression that makes the septic patient more susceptible to nosocomial infections and leads to poor clinical outcomes. MDSCs are thought to play a central role in this immune-paralysis and the dysfunction of T cells in these patients, as reviewed by Zhang et al., ⁷³ Schrijver et al., ⁷⁴ and Malavika et al. ⁷⁵ Thus, targeting MDSCs in sepsis seems an attractive idea. ⁷³ Restoration of arginine is an example of treating the effects of MDSCs, which produce Arg-1 and lead to deprivation of arginine. ⁷⁶

The implicating microorganisms may differentially induce PMN-MDSCs and M-MDSC subpopulations during sepsis, as shown by Janols et al., who observed that Gram-positive bacteria are related to increased PMN-MDSCs. ⁷⁷ The expansion of MDSCs in sepsis seems to be driven by MyD88, ⁷⁸ the transcription factors STAT3 and C/EBPβ, the protein S100A9 and the microRNAs miR-21 and miR-181b, as demonstrated in mouse models.^79–82 Patera et al. reported that M-MDSCs increase in septic patients and critically ill non-septic patients in the intensive care unit (ICU) compared to healthy donors. ⁸³ Uhel et al. also found increased counts of M-MDSCs in both septic and critically ill non-septic patients. However, PMN-MDSCs were specifically elevated in septic patients and together with important markers of their functionality (Arg-1 and S100A12) were correlated with increased incidence of nosocomial infections in the patients. ⁸⁴ Matthias et al. studied MDSCs after severe sepsis and septic shock and, according to their cohort, persistent high counts of these cells were correlated with higher incidence of nosocomial infections, prolonged stay in the ICU, and worse functional status. ⁸⁵ Darden et al. implemented single-cell RNA-sequencing in MDSCs from late sepsis patients, and their study revealed that there were three distinct subpopulations, i.e., PMN-MDSCs, M-MDSCs, and eMDSCs, which had immunosuppressive properties. ⁸⁶

However, there is the opinion that, during sepsis, regardless of the pathogen, it is essential that the systemic inflammation is restricted at some point, and, in accordance with this, Sander et al. described that MDSCs had a positive impact on survival in a mouse model of polymicrobial sepsis. ⁸⁷ Brudecki et al. also proposed that MDSCs are beneficial for the host during sepsis and display different roles during early and late stages of the condition, through proinflammatory and anti-inflammatory effects, respectively. ⁸⁸

It is proposed in the literature that the two opposite effects of MDSCs during sepsis reflect that these cells are beneficial in early sepsis, where an inflammation storm is unwanted, and deleterious in late sepsis, where immune-paralysis leads to unfavourable clinical outcomes. This may be reflected in the worse prognosis accompanied by increased counts of MDSCs in most clinical studies, and, on the other hand, the positive actions of MDSCs shown in experimental studies.^74,89 Furthermore, this opinion for the dual role of MDSCs in sepsis could be strengthened by the recent study of Schrijver et al., who enrolled critically ill patients with pneumonia and sepsis with multi-organ failure and correlated for the first time the increased counts of M-MDSCs with better survival of the patients. ⁹⁰