Here, There and Everywhere: Myeloid-derived Suppressor Cells in Immunology

Abstract

Myeloid-derived suppressor cells (MDSC) were initially identified in humans and mice with cancer where they profoundly suppress T cell and NK-mediated antitumor immunity. Inflammation is a central feature of many pathologies and normal physiological conditions and is the dominant driving force for the accumulation and function of MDSC. Therefore, MDSC are present in conditions where inflammation is present. Although MDSC are detrimental in cancer and conditions where cellular immunity is desirable, they are beneficial in settings where cellular immunity is hyperactive. Because MDSC can be generated ex vivo they are being exploited as therapeutic agents to reduce damaging cellular immunity. This article reviews the detrimental and beneficial roles of MDSC in disease settings such as bacterial, viral, and parasitic infections, sepsis, obesity, trauma, stress, autoimmunity, transplantation and graft vs. host disease, and normal physiological settings including pregnancy and neonates, and aging. The impact of MDSC on vaccination is also discussed.

Myeloid-derived suppressor cells (MDSC³) were first identified in patients with advanced cancer where they are profoundly immune suppressive cells that inhibit antitumor immunity. With the notoriety of MDSC as potent inhibitors of cancer immunotherapy and the knowledge that chronic inflammation is the dominant driving force for the development and function of MDSC, investigators in other fields in which inflammation is also prevalent have asked if MDSC are induced. The answer has been a resounding “yes,” and MDSC are now recognized as regulatory cells in many pathological settings as well as in normal physiological conditions. In contrast to cancer where MDSC are exclusively detrimental because they are potent inhibitors of natural antitumor immunity and obstacles to cancer immunotherapies, MDSC can be either detrimental or beneficial in non-cancer settings. In addition, their potent immune suppressive activity is being exploited in settings where cell-mediated immunity is damaging (Table I).

Table I.

MDSC are present in many immunological diseases and normal settings where they are either detrimental or beneficial

Disease/Condition	Human/mouse	MDSC	Beneficial/Detrimental	Comments	References
Cancer	Human, mouse	PMN-MDSC M-MDSC	Detrimental	Prevent T cell activation; inhibit T cell function; promote pro-tumor type 2 responses, metastasis, Tregs, stem cell expansion, angiogenesis	(1–5)
Bacterial infections	Mouse Staphylococcus aureus, mouse	M-MDSC, MDSC	Detrimental	Promote biofilm formation	(6, 7)
	TB, human	MDSC	Detrimental	Inhibit adaptive immunity	(8)
	TB, human	MDSC	Beneficial	Can be converted to M1 macrophages & clear TB	(9)
	Pneumonia, mouse & human	Human/mouse M-MDSC	Beneficial	IL-10 prevents lung damage, improves survival	(10, 11)
Viral infections	Human Hepatitis B & C, human	M-MDSC	Detrimental	Inhibit anti-viral T cells; drive iTregs	(12–15)
	HIV, human	M-MDSC	Detrimental	Inhibit antiviral immunity; drive Tregs	(16–18)
	SARS-CoV-2, human	M-MDSC, PMN-MDSC	Detrimental, beneficial	Suppress anti-viral T cells; reduce damaging inflammation	(19, 20)
Parasitic diseases	T. cruzi, mouse	MDSC	Beneficial, detrimental	Resolve inflammation; prevent T. cruzi induced myocarditis; prolong parasite survival	(21, 22)
	Leishmania, mouse	MDSC	Beneficial, detrimental	Suppress T cell activation; possibly promote leishmaniasis; kill amastigote stage; protect against infection	(23–25)
	Malaria, human & mouse	PMN-MDSC	Detrimental	Inhibit CD4+ & CD8+ T cells; early marker for disease; promote Th17 response	(26, 27)
	Schistosomiasis, mouse	PMN-MDSC	Detrimental	Suppress anti-Schistosome T cell responses	(28)
	Echinococcosis, mouse	MDSC	Detrimental	Inhibit Th2 cells; prevent helminth clearance	(29)
Sepsis & post sepsis immune suppression	Human	M-MDSC, MDSC	Detrimental	Suppress T cell activation and cytokine production; increased mortality due to infections; lymphopenia; high levels in early sepsis predict poor prognosis	(30–32)
Obesity	Mouse	MDSC	Beneficial	Decrease metabolic dysfunction (glucose tolerance; glucose serum levels)	(33, 34)
	Mouse	MDSC	Detrimental	Increase cancer progression	(33, 35–37)
Pregnancy and neonates	Pregnancy, mouse	PMN-MDSC	Beneficial	Facilitate implantation; maintain pregnancy	(38–41)
	Pregnancy, human	PMN-MDSC	Beneficial	Protect against pre-eclampsia; predict successful pregnancy following IVF	(42–45)
	Pre-term; normal term infants, mouse & human	PMN-MDSC	Detrimental	Increase susceptibility to infection	(46, 47)
	Newborns, pre-term infants, mouse & human	M-MDSC	Beneficial	Adoptive transfer of lactoferrin-ex vivo induced MDSC protect against pathologic inflammation	(48, 49)
Transplantation; GVHD	Human & mouse	Adoptive transfer of M-MDSC & PMN-MDSC for AlloHCT	Beneficial	Higher levels of MDSC predict less severe GVHD; higher levels correlate with less severe GVHD; M-MDSC increase Tregs; better survival rates; does not reduce GVL	(50–57)
Autoimmunity	EAE, colitis, SLE, CIA, Type1 diabetes, mouse	MDSC	Beneficial	Adoptive transfer down-regulates Th1, Th17 cytokines; promotes Tregs, MDSC expand IL-10 producing Bregs	(40, 58–66)
	Uveitis, mouse & human	M-MDSC	Beneficial	Decrease Th1 and Th17; MDSC levels correlate with remission	(61, 67)
	EAE, mouse	MDSC	Detrimental	Drive Th17 cells	(68, 69)
	Multiple sclerosis, human	MDSC	Beneficial?	Increased MDSC correlate with remission	(58)
	SLE, human & mouse	M-MDSC & PMN-MDSC	Detrimental	Drive Th17 cells; impair Treg development	(70, 71)
Stress & trauma	Stress, mouse	MDSC	Detrimental	Post-surgery stress: decrease T cell function; enhance metastasis	(72)
	Trauma, mouse	MDSC	Detrimental	Decrease T cell function	(73, 74)
	Trauma, human	PMN-MDSC	Beneficial	IL-10 reduces trauma-associated inflammation	(75)
Aging	Human	MDSC	Detrimental	Presumably decrease immunocompetence	(76)
Vaccination	BCG in mice	M-MDSC	Detrimental	Impair T cell priming in DLN	(77)
	mRNA flu vaccine in Rhesus macaques	M-MDSC & PMN-MDSC	Possibly detrimental	Invade injection site but not DLN	(78)
	HepB vaccine in obese mice	MDSC	Detrimental	Inhibit T cell proliferation and antibody production	(79)
	HIV vaccine in mice	MDSC	Detrimental	Reduce HIV-1 GAG-specific CD8+ Tcells; induced MDSC are HIV-infected and PD-L1+	(80)
	Parasite infected humans	MDSC	Potentially detrimental	In endemic areas of parasite infection individuals may have infection-induced MDSC	(81)
	T. cruzi vaccine in mice	MDSC	Detrimental	MDSC depletion enhances vaccine efficacy	(82)
	Ovarian cancer vaccine in mice	MDSC	Detrimental	MDSC depletion yields antitumor CD8+ T cells	(83)
	HPV-targeted vaccine for multiple HPV+ tumors in mice	MDSC	Detrimental	Sunitinib depletion of MDSC increases HPV E7-specific CD8+T cells and survival	(84)
	DC wild type p53 vaccine in small cell lung cancer patients	MDSC	Detrimental	ALTRA depletion of MDSC increases p53-reactive CD8+ T cells	(85)

Historically, MDSC have predominantly been characterized in mouse and human cancer, but MDSC in other settings appear to share similar key characteristics. As it has become apparent that MDSC are involved in many immunological processes, MDSC development and function are also being explored in non-cancer immune conditions. We will briefly summarize the salient features of MDSC and will then focus on MDSC in settings other than cancer. More detailed descriptions of the development and function of cancer-induced MDSC can be found in several excellent recent reviews (1–5).

MDSC characteristics and induction

MDSC are a diverse population of myeloid cells that span the differentiation pathway of the common myeloid progenitor (CMP) cell. MDSC accumulation is initiated when NOTCH and IRF8 are downregulated and “emergency myelopoiesis” occurs. The expansion of MDSC occurs at the expense of other cells in the CMP lineage.

There are two dominant phenotypes of MDSC: monocytic (M-MDSC) and polymorphonuclear or granulocytic (PMN-MDSC). In mice MDSC are phenotypically identified as Gr1⁺CD11b⁺ cells with M-MDSC being CD11b⁺Ly6C⁺Ly6G⁻ and PMN-MDSC being CD11b⁺Ly6G⁺Ly6C^−/low. Neutrophils also have the latter phenotype in infectious disease settings. In humans MDSC are CD33⁺CD11b⁺HLA-DR^low/- with M-MDSC being CD14⁺CD15⁻ and PMN-MDSC CD15⁺CD14⁻CD66b⁺. Cells with a third phenotype termed early stage MDSC (eMDSC) are present in humans; these are CD33⁺CD11b⁺ and lack other myeloid markers. The absence of HLA-DR distinguishes human MDSC from monocytes. MDSC are primarily identified by the immune regulatory molecules they produce. M-MDSC generate nitric oxide synthase (NOS2), NO, TGFβ, and IL-1β. PMN-MDSC contain NOX2 and reactive oxygen species (ROS, H₂O₂, O₂⁻). Both types of MDSC can produce Arginase 1 (Arg1), peroxynitrite (ONNO⁻), prostaglandin E2 (PGE2), and IL-10. These phenotypic markers in combination with assays demonstrating functional suppression of T cells (e.g., inhibition of T cell proliferation, T cell activation including IFNγ or IL-2 production, T cell CD3ζ downregulation, and for CD8 T cells, T cell cytotoxic activity) are the defining but not exclusive parameters of MDSC (86). (Fig. 1)

Figure 1.

Myeloid-derived suppressor cells are predominantly induced by proinflammatory mediators and by some non-inflammatory molecules and are naturally present in many pathological and normal settings. MDSC are also induced ex vivo and used for adoptive transfer to down-regulate undesirable immune responses. Multiple proinflammatory and a few non-inflammatory molecules in combination with adrenergic signaling drive the accumulation and suppressive function of MDSC, including GM-CSF, PGE2, IL-6, VEGF, S100A8/A9, TNF-α, G-CSF, IL-1β, HMGB1, leptin, adenosine, lactoferrin, and oxidized lipids. PMN-MDSC and M-MDSC both use Arg1, PGE2, peroxynitrite (ONNO⁻), and IL-10 to suppress T cell activation and function, while PMN-MDSC also use hydrogen peroxide (H₂O₂), superoxide (O₂⁻), and NOX2, and M-MDSC also use NO, TGFβ, and IL-1β.

In the presence of inflammation in general, as well as certain non-inflammatory molecules, MDSC expand and gain increased suppressive potency. Pro-inflammatory cytokines including IL-6, IL-1β, TNFα, VEGF, GM-CSF, and G-CSF, the bioactive lipid prostaglandin E2, the DAMP/alarmins HMGB1 and S100A8/A9, all up-regulate MDSC, as do the non-inflammatory molecules adenosine (87), lactoferrin (48), and leptin (33). In combination with adrenergic signaling these molecules activate MDSC through the STAT3 and NF-κB pathways. In the tumor microenvironment (TME), inducers are produced by tumor cells or are generated by the hypoxic TME resulting in activation of an ER stress response (reviewed in (2)). (Fig. 1).

MDSC immunometabolism

MDSC exist in the circulation of healthy individuals at low levels. When they enter the TME or other proinflammatory locales they undergo metabolic changes. Within the TME MDSC become dependent on the uptake of lipids and fatty acid oxidation (FAO). Polyunsaturated fatty acids increase the differentiation of mouse MDSC and up-regulate MDSC suppressive activity by increasing ROS production via JAK-STAT3 signaling (88). Pharmacologic inhibition of fatty acid uptake and FAO reduces mouse and human MDSC suppressive potency and reprograms MDSC to contain more mitochondria, synthesize enzymes essential for FAO, increase oxidation rate (89, 90), and increase expression of fatty acid transport proteins (FATP) (91). G-CSF and GM-CSF induce mouse and human MDSC by up-regulating the expression of lipid transport receptors such as FATP2 and fatty acid metabolic pathways via STAT3 and STAT5 signaling. Increased FATP2 expression in PMN-MDSC facilitates the uptake of arachidonic acid which is converted intracellularly to PGE2 (92), a dominant driver of MDSC suppressive potency (93, 94). This suppressive activity is enhanced by mast cells (95). Metabolic driven accumulation of methylglyoxal also increases the suppressive activity of MDSC (96) as described in the “suppressive mechanisms” section below.

MDSC circulating in blood use oxidative phosphorylation for energy generation but convert to glycolysis (Warburg effect) when they enter the hypoxic TME (97). Immunometabolic and single cell RNAseq studies of MDSC demonstrate that maturation and the acquiring of increased suppressive potency requires aerobic glycolysis and the consumption of high levels of glucose. However, MDSC themselves consume large amounts of glucose and their limited life span in vivo is likely due to insufficient quantities of glucose (6).

MDSC suppressive mechanisms

As alluded to above, MDSC use multiple mechanisms to suppress adaptive and innate immunity. MDSC are best known for their ability to inhibit T cell activation and function. They produce Arg1 and indoleamine 2,3-dioxygenase (IDO) and sequester cysteine thereby limiting the availability of L-arginine, cystine and tryptophan, amino acids essential for T activation (98–100). MDSC also deplete T cells of essential L-arginine by their accumulation of the metabolite methylglyoxal which they transfer to T cells. Within T cells, methylglyoxal glycates L-arginase thereby rendering it unusable by T cells (96).

MDSC produce ROS and NOS2 to generate peroxynitrite which nitrates TCRs, MHC molecules, and chemokines preventing T cell recognition of tumor antigens and blocking T cell chemotaxis (101, 102). Although MDSC produce high levels of ROS they are not themselves affected due to their upregulation of nuclear factor erythroid-2 (Nrf2) which controls a battery of antioxidant genes (103). L-selectin is essential for naïve T cells to enter lymph nodes and become activated. MDSC perturb this trafficking by their expression of ADAM-17 which cleaves L-selectin (104, 105). MDSC are also potent inducers of T regulatory cells (Tregs) through their production of indoleamine 2,3, dioxygenase (IDO), TGF-β, and IL-10 (106). Engagement of MDSC-expressed PD-L1 and galectin-9, ligands for the T cell inhibitory receptors PD-1 and Tim-3, respectively, drives T cell exhaustion and arrest (107, 108). Activated T cells can defend themselves against PD-L1⁺ MDSC through their expression of FasL which mediates apoptosis of Fas⁺ MDSC (109). As MDSC accumulate and differentiate they synthesize S100A9 thereby skewing myeloid cell differentiation towards MDSC and away from dendritic cells (DC), resulting in diminished availability of cells for antigen processing and presentation for T cell activation (110).

MDSC also inhibit humoral immunity. Their production of Arg1, NO, and ROS decreases B cell IgM responses and induces B cell death (111), and their synthesis of TGF-β down-regulates IL-7 production and downstream STAT5 signaling which are essential for B cell development (112).

Innate immunity is also inhibited by MDSC. MDSC express membrane-bound TGF-β1 which inhibits NK cell expression of NKG2D and reduces NK cell production of IFNγ thereby anergizing NK cells (113). MDSC production of IL-10 drives the polarization of macrophages towards an M2-phenotype which promote tumor progression (114).

Many of the suppressive mediators are transported in exosomes and include proteins, glycoproteins, miRNAs, and mRNAs (115, 116). MDSC activity does not involve specific receptors; however, cell-to-cell proximity is required, presumably due to concentration effects of secreted/released materials. Given the diversity of MDSC, it is likely that their phenotype and function vary depending on the physiological setting, so that not all suppressive mechanisms are relevant in all settings. Fig. 2 summarizes the suppressive mechanisms used by MDSC.

Figure 2.

Immune suppressive mechanisms used by MDSC. MDSC use a variety of mechanisms involving secreted molecules, membrane-bound molecules, cytokines, and metabolic reprogramming to suppress T cells, B cells, and innate immune effector cells. T cell mechanisms are shown in brown boxes, B cell mechanisms in purple boxes, and innate mechanisms in red boxes.

Relationship of MDSC to neutrophils and inflammatory monocytes

PMN-MDSC and M-MDSC share some characteristics with neutrophils and inflammatory monocytes, respectively. Whether MDSC are a distinct population of cells or are a subset of neutrophils or inflammatory monocytes remains controversial. MDSC were originally defined by their phenotype, their accumulation under pathological (cancer) conditions, and their exceptional ability to inhibit T cell activation and function (117). Other myeloid cells including tumor-associated neutrophils and tumor-associated macrophages share some of these properties with MDSC. However, studies have identified the lectin-type oxidized LDL receptor 1 (LOX1) (118) and the fatty acid transport protein 2 (FATP2) as specific markers for PMN-MDSC (5). M-MDSC, which phenotypically resemble inflammatory monocytes, can differentiate into tumor-associated macrophages (119) and fibrocytes (120), activities that are not associated with classical monocytes. Likewise, some of the mechanisms used by MDSC to suppress T cell activation and function, such as cysteine deprivation (99) and L-selectin down-regulation (104) are not functions of neutrophils or monocytes, and single cell transcriptional analyses of PMN-MDSC and tumor-associated neutrophils have identified transcriptomes specific for each cell type (121). These differences do not speak to the relationship between MDSC, neutrophils, and inflammatory monocytes; however, they define MDSC as a functionally distinct cell population. Many reports define MDSC without using the full repertoire of MDSC characteristics, so there is some ambiguity as to whether the cells are full-fledged PMN-MDSC or neutrophils, or M-MDSC or other monocytes. In this article, MDSC are defined as cells with the established phenotype and demonstrated immune suppressive activity.

Some of the following studies distinguish between PMN-MDSC and M-MDSC; however, other studies have not separated the two populations. If studies identified PMN-MDSC and M-MDSC, then the specific identification is used. However, if reports do not separate the two subtypes, then we use the terminology “MDSC.”

Bacterial and viral diseases

MDSC expand in response to inflammation in all bacterial and viral diseases studied to date. The initial expansion of MDSC presumably protects the host against excessive inflammation. However, if MDSC persist, they inhibit the anti-pathogen function of T and NK cells, leading to reduced pathogen control and increased disease progression. Therefore, MDSC can have both protective and detrimental functions.

Bacterial infections

MDSC play both detrimental and beneficial roles in bacterial infection with MDSC-derived IL-10 being a key factor. Metabolic profiling demonstrated that limited amounts of environmental glucose in invasive S. aureus disease inhibits the differentiation of MDSC into more mature non-suppressive cells (6). Nonetheless, MDSC generated in S. aureus infection produce IL-10 which supports biofilm formation (7). In contrast, M-MDSC-derived IL-10 promotes clearance of Klebsiella pneumoniae in mice and reduces inflammation, thereby improving host survival (10, 11). MDSC also accumulate in patients infected with Mycobacterium tuberculosis (Mtb) as well as in individuals recently exposed to Mtb (8). The MDSC typically inhibit immunity to Mtb. However, if their leukocyte immunoglobulin-like receptor B is blocked by antibody, then human MDSC are converted to M1-type macrophages which mediate the intracellular killing of Mtb (9).

Viral infections

In general, MDSC play a detrimental role in viral infections and the generation and maintenance of antiviral immunity. M-MDSC accumulate in blood and the liver of hepatitis B patients where they inhibit antiviral T cell responses (12). M-MDSC-derived IL-10 promotes the development of iTregs which further inhibit antiviral immunity (13). These findings have been replicated in chronic hepatitis C patients (14, 15). In HIV-infected individuals, M-MDSC accumulate in response to IL-6 and drive Treg levels via their production of IL-10 (16). The persistence of immune dysfunction in AIDS patients on combined antiretroviral therapy is thought to be due to the persistence of M-MDSC (17).

M-MDSC accumulate in the blood of SARS-CoV-2-infected patients with both mild and severe disease (122, 123). Higher levels of M-MDSC and PMN-MDSC at the time of hospital admission are predictive of severity (19) and recovery is associated with reductions in MDSC (122). PMN-MDSC similarly expand in patients with severe acute respiratory distress syndrome accompanying SARS-CoV-2 infection (20), and correlate with COVID-19-associated lymphopenia. The continued accumulation of MDSC parallels fatal disease, although it is unclear if MDSC contribute to fatality through their inhibition of antiviral immunity (124). COVID-19-induced MDSC suppress T cell activation in vitro and as for other pathogens, the anti-inflammatory and immune suppressive functions of MDSC work antagonistically in that they limit the damaging inflammation, but at the same time suppress antiviral immunity. Transcriptional analysis suggests that PMN-MDSC of COVID-19 patients with severe disease have increased Arg1 expression relative to symptomatic patients. People who die from COVID-19 have large infiltrates of Arg1⁺ PMN-MDSC in their lungs, suggesting that ROS production by PMN-MDSC may contribute to lung pathology (125). In patients with asymptomatic or mild disease, MDSC remain elevated for at least three months post-recovery (126). Given the excessive levels and persistence of MDSC it is questionable if new T cells are activated in immunized patients who succumb to SARS-CoV-2 infection, or if resolution of the disease is due to adaptive immunity induced pre-disease by vaccination.

Parasitic and fungal diseases

Myeloid cells are key players in anti-parasitic immunity with different roles in protozoan and metazoan infections. Although not extensively studied, it has been reported that MDSC are produced in tandem with enhanced myelopoiesis during several parasitic infections (127). MDSC are also considered to be part of “trained” immunity during fungal infections including Aspergillus (128), Candida (128–130) and Cryptococcus (131). The effects of MDSC on immunity to complex pathogens can be detrimental in some infections where T cell-mediated immunity is protective. For example, arginase inhibitors, specifically the p38 inhibitor SB202190 or the receptor tyrosine kinase vandetanib, suppress PMN-MDSC in Cryptococcus neoformans fungal infection and enhance protective T cell responses (131).

MDSC, particularly M-MDSC, play a key role in Kinetoplastid infections. In mouse models they resolve inflammation during Trypanosoma cruzi acute infection (21, 22) and prevent T. cruzi infiltration of the heart causing Chagas-associated myocarditis (132). A cellular therapy with mesenchymal stem/stromal cells overexpressing the MDSC inducer G-CSF increased MDSC migration to the heart (133) where they suppressed cardiac pathology. MDSC suppress T cell function by both Arg1 (22) and NO (134). In mouse T. cruzi infection suppression prolongs parasite survival in heart tissue. In Chagas, MDSC alter ROS and NO-mediated mechanisms of T. cruzi parasite killing (22). In contrast, MDSC in Leishmaniasis expand in response to parasite antigen (23) and suppress T cell proliferation (23, 24) possibly contributing to progressive visceral leishmaniasis (25). Surprisingly, the NO induced in MDSC is lethal to intracellular amastigote stages and protects against propagation of infection (24). On the other hand, glycyrrhizic acid inhibits Cox-2-mediated MDSC suppression and restores T cell proliferation leading to control of parasite numbers in BALB/c mice (23).

There is little information on MDSC in Apicomplexan infection. This is surprising given the burden of malaria, the recent surge in understanding Cryptosporidium with the emergence of a tractable model of study, and the historically strong focus on Toxoplasma. An initial report described the generation of PMN-MDSC in controlled human malaria challenge with P. falciparum and their suppression of CD3/CD28-mediated T cell proliferation (26). A recent paper indicates the presence of potential MDSC populations in PBMCs during naturally acquired infections with severe P. falciparum and uncomplicated P. vivax malaria, albeit suppressive capacity was not tested (135). Splenic MDSC populations, in particular NO-expressing PMN-MDSC, expand in C57BL/6 mice infected with P. berghei ANKA (27), a mouse model of cerebral malaria. Expansion was dependent on STAT3 signaling emanating from the IL-6 receptor and correlated with promoting Th17 responses. The significance of this finding is unclear because other studies suggest that neurological manifestations of P. berghei ANKA in mice are independent of IL-17 (136).

Schistosoma japonicum worm antigen and egg antigen also drive differentiation of MDSC via STAT3 (137) with ROS-dependent suppression on anti-Schistosome T cell responses (28). Similarly PD-L1 expression by PMN-MDSC have been suggested to suppress anti-Schistosome Tfh1 cells (28), potentially impacting anti-Schistosome humoral immunity. MDSC also expand in Echinococcus granulosus infection of BALB/c mice (138). These MDSC use NO to suppress Th2 cell development that drives anti-helminth mechanisms of clearance (29). E. granulosus-driven MDSC have elevated transcription of VEGF and induce angiogenesis in cultured HUVECs (139). Furthermore, multiple miRNAs involved in immunoregulatory pathways (139) as well as long coding RNAs (140) are enriched in MDSC from E. granulosus infected mice.

Mast cells impact MDSC function in parasitic disease

Mast cells are key mediators in parasite expulsion, but they effect MDSC function which can feed back into anti-parasite immunity. In the TME, mast cells augment accumulation of M-MDSCs (141, 142), in part through histamine released during mast cell degranulation (143). However, mast cells are critical mediators of parasite expulsion and PMN-MDSC enhance anti-parasitic immunity and have been correlated with elevated levels of the Th2 cytokines IL-4, IL-5, IL-13 (144) as well as IL-17 and the alarmin IL-33. Depletion of MDSC by gemcitabine enhanced infection with the rat hookworm Nippostrongylus (144) and the nematode Trichinella spiralis (145). Although off-target effects of gemcitabine were assessed, there was no separation of neutrophils from PMN-MDSC making it difficult to separate effects of PMN-MDSC from the protective effects of NETS produced from mature neutrophils in the Nippostrongylus model (146). This point is pertinent because of the role of mast cell tryptase in the induction of neutrophil NETS (147). Nonetheless, the enhancement of IgE-mediated mast cell function, a key mechanism in mast cell activation during helminth infection, suggests how MDSC augment immunity to intestinal helminths. This activity may also impact other infections such as malaria, where the role of mast cell degranulation promotes parasite survival in the P. berghei ANKA mouse model in some (148) but not all (149) genetic backgrounds.

Sepsis and post-sepsis immune suppression

Sepsis results when innate immunity over-responds to infection and the release of pro-inflammatory cytokines and chemokines causes cardiovascular dysfunction and organ destruction. Hyper-inflammation, cytokine release syndrome, tissue hypoxia, hyper-coagulation, and endothelial cell destruction, are other potentially lethal events (150). Medical advances have improved survival of patients with acute sepsis; however, sepsis survivors can have long-term complications including chronic inflammation, immune suppression, tissue wasting, and lymphopenia. A study of 74 patients with severe sepsis/septic shock detected increasing levels of MDSC throughout the 28 day study period (151), and high levels of MDSC during early sepsis are predictive of a poor prognosis (32). Chronic immune suppression in post severe sepsis/septic shock patients has a poor clinical prognosis due to infection and is associated with abnormal myelopoiesis and the accumulation of MDSC (152, 153).

Studies of post-surgical sepsis patients underscore the detrimental effects of MDSC, particularly M-MDSC, in suppressing immunity to infection. In 267 survivors of surgical sepsis, MDSC levels were elevated for at least 6 weeks post infection (30), suppressed antigen-driven T cell proliferation and cytokine production and led to increased nosocomial infections. Cardiac surgery patients with elevated levels of M-MDSC had higher incidences of post-surgery sepsis-induced immune suppression and subsequent mortality due to infection (154). Elevated levels of M-MDSC were similarly found to predispose to sepsis-induced immune suppression and mortality due to infection in 301 septic shock patients, 50 of whom exhibited post septic shock immune suppression (31). A single cell RNA sequencing study of MDSC from two 21-day post-sepsis patients and two healthy controls identified common transcripts as well as transcripts unique to post sepsis MDSC, suggesting that post sepsis MDSC may have a distinct transcriptome (155).

Studies in mice have provided mechanistic insight into MDSC in sepsis. A study using cecal ligature and puncture followed by polymicrobial infection demonstrated that late phase MDSC accumulate in the vasculature of non-lymphoid tissues including the lungs (156). In the same model, COX2 (157) and S100A9 (158) are key drivers of MDSC in post-sepsis immune suppression, and in a mouse LPS-induced sepsis system Nrf2 is essential for MDSC survival (159). In a neonatal sepsis model (bacterial infection of 3–4-day old mice) MDSC contain elevated transcripts for NOS2, Arg1, and IL-27p28 and express TLRs 2,4, and 5 which recognize multiple pathogen-associated molecular patterns of E. coli (160).

Obesity

The chronic presence of multiple pro-inflammatory mediators such as IL-6, TNFα, PGE2, and IL-1β in obesity is reminiscent of the TME. Since these molecules are also inducers of MDSC, it is not surprising that MDSC are elevated in obese patients (161, 162). Mice that become obese through consumption of a high fat diet (HFD) have elevated levels of MDSC in their circulation and adipose tissue, and tumor growth is accelerated (33, 37, 163). Although MDSC-like cells are elevated in morbidly obese patients and the levels decrease following bariatric surgery, these cells have low levels of ROS and do not suppress T cell proliferation (164). Therefore, not all MDSC in obese individuals have the same characteristics.

Obesity is a risk factor for cancer development and progression (165–167). The discovery of MDSC in obese individuals led to the concept that immune suppression by MDSC contributes to cancer risk (36) and studies in tumor-bearing obese mice, including breast (39), ovarian (35), and renal (37) cancers support this hypothesis.

Diabetes can also be a consequence of obesity and is characterized by elevated fasting glucose levels and high insulin. High fat diet (HFD) obese mice have elevated TNF-α in the circulation and adipose tissue and elevated blood glucose and are insulin resistant. Depletion of MDSC further increased blood glucose levels and insulin tolerance indicating that these cells protected the mice against more extreme metabolic dysfunction, while concomitantly enhancing tumor progression (33, 34). Leptin is produced by adipose cells in response to inflammation and is an appetite suppressant in non-obese healthy individuals. It regulates the balance between metabolism and food intake and is frequently over-expressed in obese individuals who become non-responsive to its regulatory function. Leptin levels are elevated in the blood of HFD obese mice. Depletion of MDSC increases leptin levels and blocking the leptin receptor in HFD obese mice lowers circulating MDSC levels. Hence, leptin serves as a driver for MDSC accumulation while MDSC down-regulate leptin levels (33).

Pregnancy and neonates

During healthy pregnancies women are tolerant to their semi-allogeneic fetus, a phenomenon known as maternal-fetal tolerance. It is likely that multiple mechanisms are responsible for maternal-fetal tolerance. MDSC appear to be one of the key mechanisms. PMN-MDSC are present in human cord blood, accumulate in the peripheral blood and endometrium during healthy pregnancies, and are diminished in women experiencing spontaneous abortions and miscarriages (168, 169). Following parturition, blood PMN-MDSC levels decrease. Pregnancy-associated PMN-MDSC suppress T cell activation, contain Arg1 and NOS2, produce large amounts of ROS, and polarize CD4⁺ T cells towards a Th2 phenotype (170, 171). Decreases in MDSC during early miscarriage track with declines in estrogen and progesterone and the diverting of CD4⁺ T cells away from a Th2 phenotype and towards a Th1 phenotype, although it is unclear if these effects are linked to MDSC levels (172).

Studies in mice demonstrated PMN-MDSC infiltration into the uterus of pregnant females. The MDSC are activated via STAT3 and used ROS to suppress T cell activation (40, 41). Depletion of MDSC early in gestation caused implantation failure, enhanced T cell activation, and increased T cell migration into the uterus. Induction of MDSC by G-CSF reversed these effects. Naïve T cells of pregnant mice had reduced L-selectin and were impaired in their ability to enter lymph nodes and become activated (39). Mice that contain HIF-1α-deficient myeloid cells contain fewer uterus MDSC, decreased implantation rates, and increased abortions, indicating that hypoxia in the uterus is critical for the development of MDSC and successful pregnancy (38).

PMN-MDSC-deficiency contributes to pre-eclampsia in women. PMN-MDSC express the HLA-G receptors ILT2 and ILT4 which are increased during pregnancy. A soluble form of HLA-G increases PMN-MDSC suppressive potency by activating STAT3 (44). Mouse studies using Qa-2, the mouse analog of human HLA-G, demonstrated that Qa-2-deficiency resulted in a pre-eclampsia-like condition and abortion that was reversed by soluble HLA-G (42). In a meta-analysis study elevated circulating levels of PMN-MDSC were associated with and predictive of a more favorable outcome for women undergoing in vitro fertilization (43, 45).

PMN-MDSC are also present in preterm and normal term infants but decrease rapidly after the 28-day neonatal period. Preterm delivery is a major cause of perinatal morbidity and mortality, and neonates are typically highly susceptible to infection. The presence of MDSC may contribute to these conditions (46, 47). However, mouse studies indicate that MDSC may also play a protective role in that their transitory presence down-regulates potentially lethal inflammatory conditions that can occur in newborns (48, 49).

GVHD and transplantation

Acute and chronic graft vs. host disease (GVHD) is the dominant complicating factor for hematopoietic stem cell transplant (alloHCT), while host vs graft responses are the major deterrent for successful solid organ transplantation. MDSC naturally occur in alloHCT; however, the levels are insufficient to prevent GVHD. AlloHCT into irradiated recipients produces an inflammatory environment conducive to MDSC development. M-MDSC and PMN-MDSC are associated with reduced incidence of acute GVHD in humans (50, 51) and adoptive transfer of M-MDSC protects against acute GVHD in mice (52). Likewise, increased M-MDSC in post-transplant renal patients may protect indirectly against host vs graft rejection by induction of Tregs (53). Therefore, MDSC have the potential to play an important role in reducing unwanted immune responses in transplant settings.

Exploiting MDSC for improving transplantation efficacy

The immunosuppressive activity of MDSC led to studies aimed at using in vivo induction or adoptive transfer of in vitro-generated MDSC for combating GVHD in alloHCT and for minimizing host vs graft responses in solid organ transplantation (173, 174). Early mouse studies used GM-CSF in combination with G-CSF to expand MDSC from bone marrow which were then adoptively transferred into allogeneic mice providing proof-in-principle of this strategy (56). Dexamethasone in combination with GM-CSF extends survival of allogeneic cardiac transplants in mice via MDSC that increase Tregs and use NOS2 to suppress T cell function (175). A comparison of naturally occurring MDSC, GM-CSF-induced MDSC and G-CSF-induced MDSC in a mouse cardiac transplant model identified G-CSF as most effective in extending graft survival (176). GM-CSF also expands MDSC from human cord blood CD34⁺ cells and inclusion of SCF generates more robust MDSC. In a xenogeneic NSG mouse system adoptive transfer of these human MDSC decreases GVHD and up-regulates Tregs (177). Thus, multiple strategies have been used to generate MDSC in mouse and human settings.

Clinical studies

Clinical data support a role for MDSC in limiting GVHD in transplant settings. Post-transplant treatment with cyclophosphamide improved PMN-MDSC generation, maintenance, and suppressive activity and reduced grade II to IV acute GVHD in children undergoing alloHCT (MCC Protocol #19295) (54). AlloHCT patients adoptively transferred with cells from pegylated-GCF mobilized MDSC had reduced rates of grade III-IV acute GVHD compared to patients given non-pegylated GCF-mobilized MDSC, suggesting that pegylation increased MDSC half-life. Overall survival rates did not differ between the pegylated and non-pegylated groups; however, pegylation may reduce the number of MDSC transfers and enhance MDSC function when using growth factor-induced MDSC (178).

Studies have also focused on location of both solid organ and alloHCT grafts to determine if MDSC suppress at the graft site or systemically. CCR2-mediated migration of MDSC to the graft site is critical in a mouse allogeneic islet transplant system and resulted in site-specific inhibition of CD8⁺ T cell function and enhancement of Tregs (179). Adoptive transfer of γδ Th17 cells in a mouse alloHCT model increases MDSC suppressive potency and drives infiltration of MDSC into the inflamed intestine thereby reducing local GVHD (180). In a mouse allo-cardiac transplant model, MDSC activation requires host NKT cells and their production of IL-4 (181), and umbilical cord mesenchymal stromal cells secreting HLA-G enhance MDSC generation, suppressive activity and ability to reduce acute GVHD in a mouse alloHCT system (55). Thus, other cells influence MDSC activation and function and graft location may dictate MDSC efficacy.

MDSC in graft vs. leukemia (GVL)

In patients with leukemias it is essential that GVHD be reduced but the GVL effect be maintained. This outcome requires that MDSC suppress GVHD without impacting the GVL response, a requirement that is supported by several studies (55, 56). This observation is perplexing because MDSC are neither antigen specific nor MHC-restricted. A report using mouse models of allo-T cell transfer into lethally irradiated recipients followed by engrafting with tumor cells suggests that NKG2D⁺ CD8⁺ T cells with a memory phenotype are essential for elimination of leukemic cells and are resistant to MDSC-mediated suppression (57), providing a potential explanation for how GVHD can be reduced by MDSC therapy without diminishing the GVL response.

Autoimmunity

Autoimmune diseases are typically associated with local chronic inflammation and the activation of autoreactive CD8⁺ T cells coupled with excessive differentiation of CD4⁺ Th1 and Th17 cells and inhibition of protective Tregs. MDSC are often present in animal models of autoimmunity and in patients with autoimmune diseases but do not completely prevent pathology. In several autoimmune conditions MDSC arise spontaneously prior to remission, and some mouse models indicate that MDSC may down-regulate pathogenic Th1 and Th17 cells, suggesting that MDSC may contribute to resolution of disease. However, there are also studies suggesting that MDSC may exacerbate autoimmunity. Therefore, whether MDSC can be exploited as therapeutic agents is controversial.

Beneficial effects of MDSC in autoimmune diseases

Most studies use adoptive transfer of MDSC into mice with an established autoimmune disease. Experimental autoimmune encephalomyelitis (EAE) is an accepted mouse model for multiple sclerosis (MS). Mice are immunized with myelin oligodendrocyte glycoprotein (MOG) 35–55 and develop antigen-specific Th1 and Th17 cells. EAE mimics human MS in that there are cycles of disease and remission. Plasmacytoid DC suppress MDSC accumulation in EAE (182); however, glycolipid-activated iNKT cells favor the accumulation of MDSC (183). Adoptive transfer of syngeneic MOG-induced MDSC into EAE mice reduces EAE severity by down-regulating myelin-reactive Th1 and Th17 cells. PD-L1 expression by the transferred MDSC is essential for disease remission in mice and probably in SLE patients (58). B cell production of GM-CSF increases EAE severity. PMN-MDSC are beneficial in that they down-regulate B cell synthesis of GM-CSF. MS patient data support a role for PMN-MDSC B cell interactions since cerebral spinal fluid frequencies of CD138⁺ B cells negatively correlate with PMN-MDSC and cytokine levels (184).

B regulatory cells (Bregs) play an important role in some autoimmune diseases by their production of IL-10 which down-regulates proinflammatory cytokines and drives Treg differentiation (185). C57BL/6 female Roquin^san/san mice spontaneously develop systemic lupus erythmatosis (SLE). IL-10-secreting Bregs expand when co-cultured with MDSC and their adoptive transfer into SLE mice decreases renal pathology by reducing anti-DNA antibodies, effector B cells, germinal center B cells and follicular Th1 and Th17 cells (64). As with EAE, expression of PD-L1 is important for MDSC-mediated protection against SLE (186).

Similar MDSC protective effects are seen in mice with dextran sodium sulfate and/or 2,4,6 trinitrobenzene sulfonic acid-induced autoimmune colitis (66). Adoptively transferred MDSC suppressed T cell activation in vitro and decreased intestinal inflammation, IFNγ, IL-17, and TNF-α (60). Autoimmune uveitis is induced in mice by immunization with the retina-specific antigen interphotoreceptor retinal binding protein in CFA followed by an injection of pertussis toxin. M-MDSC increase in these mice during and before spontaneous resolution of disease and adoptive transfer of these M-MDSC accelerates remission and reduces Th1 and Th17 cells. Similar increases in M-MDSC were associated with disease remission in patients with autoimmune uveitis (61). Adoptive transfer of mesenchymal stem/stromal cells to mice with uveitis also increased MDSC levels resulting in decreased Th1 and Th17 cells (67).

Collagen-induced arthritis (CIA) in mice is a model for human rheumatoid arthritis and is initiated by injection of Type 2 xenogeneic collagen in IFA. MDSC develop spontaneously in CIA mice by day 35 post initiation of CIA but do not prevent disease. However, if splenic PMN-MDSC, M-MDSC, or total MDSC from CIA mice are adoptively transferred into CIA mice at day 21 post CIA induction, then arthritis symptoms are reduced. MDSC production of IL-10 is essential for the therapeutic effect and acts by increasing Tregs and down-regulating Th17 cells, TNF-α, IL-6 and IFNγ (59, 63). Adoptive transfer of MDSC in a mouse model of psoriasis diminished imiquimod-induced skin inflammation by reducing TNF-α and IFN-γ and by increasing Tregs (62). Likewise, adoptive transfer of MDSC reduced or prevented the onset of diabetes in 60% and 70%, respectively in a Type 1 transgenic NOD mouse diabetes model (65).

Detrimental effects of MDSC in autoimmune diseases

Although many mouse models suggest that MDSC protect against autoimmune-induced inflammation, contrasting studies indicate that MDSC may exacerbate autoimmunity by enhancing Th17 differentiation. In a MOG EAE study, the MDSC suppressed T cells in vitro, but lost potency when adoptively transferred and instead enhanced the differentiation of Th17 cells increasing disease severity. Depletion of these MDSC reduced disease severity (68, 69). In SLE patients, M-MDSC and PMN-MDSC correlate with disease severity and increase Th17 cell differentiation in vitro. Studies with humanized mice confirmed that SLE-induced MDSC drive the differentiation of Th17 cells through an Arg1-dependent process (70). Other studies in MRL/lpr mice with SLE have confirmed that adoptive transfer of PMN-MDSC impairs Treg development while M-MDSC promote Th17 polarization via IL-1β (71). In a mouse CIA model MDSC promoted Th17 differentiation through an IL-1β-dependent process (187). The MDSC in this study are osteoclast progenitors that facilitate arthritis bone resorption. MDSC in NOD mice decreased Th2 responses and depletion of MDSC improved Sjögren-like autoimmune symptoms (188).

Stress and trauma

Chronic stress can diminish cell-mediated immunity. The decrease in immunocompetence is commonly attributed to glucocorticoids and catecholamines via T cells that have receptors for these hormones, thus polarizing the T cells towards type 2 immunity. However, stress also induces IL-6, IL-1 and VEGF (189), raising the possibility that MDSC may contribute to stress-induced immune effects.

Physical and psychological stress

Stress studies in patients are challenging because of the difficulty in evaluating the severity of stress and the multiple conditions that lead to it. In cancer, stress can accompany the period immediately following removal of primary tumor and is associated with decreased T cell function which may contribute to metastasis. Mouse breast cancer studies indicate that removal of primary tumor increases MDSC and enhances metastasis (72), supporting the hypothesis that metastasis increases post-surgery due to the accumulation of MDSC. However, a clinical trial (NCT#03578627) of 16 patients following breast cancer surgery indicated that circulating MDSC levels do not increase in the period immediately after surgery but are elevated in post-surgery patients experiencing additional life-induced stress factors (190).

Physical conditions such as crowding, food and/or water deprivation, and improper day/night lighting have been used to induce physical and psychological stress in animal models. In a mouse restraint model stress-induced IL-6 led to an increase in PMN-MDSC via STAT3 signaling, an effect that was reversed by administration of β-adrenergic inhibitors (191–193).

Trauma

Clinical studies suggest that MDSC differentiation is induced following trauma-induced inflammation but indicate the MDSC may be beneficial in the immediate aftermath of the incident. Patients with mild to severe trauma develop high intracellular ROS and elevated levels of activated PMN-MDSC. Because MDSC produce the anti-inflammatory cytokine IL-10, they downregulate trauma-associated inflammation by decreasing Th17 and Th1 cells (75). Immune deficiency can occur following a severe traumatic event and patients can succumb to infection (194) possibly via MDSC-mediated T cell suppression. In a mouse model of abdominal trauma, splenic MDSC were elevated 6–72 hours following the initiation of trauma and T cell dysfunction ensued via an Arg1-dependent mechanism (73) supporting this hypothesis. In rat femur fracture and polytrauma models, MDSC levels peaked in the spleen 2 hrs after initiation of trauma, returning to normal within 6–18 hrs. MDSC also increase in a mouse pseudofracture trauma model where neutralization of the DAMP HMGB1 reverses the MDSC increase and restores T cell function (74).

Aging

As laboratory mice age hematopoiesis becomes skewed towards myelopoiesis and this is associated with increased differentiation of functional MDSC (195). Myeloid skewing also occurs in humans (196) but whether functional MDSC are increased with age in the absence of pathology remains unclear. The wealth of mouse data is matched by knowledge of human MDSC in cancer, but not in healthy aging, although sparse data suggest there may be parallels with the mouse. Despite the many reviews on this topic, the marked differences between humans and mice (197) are not usually made clear. Hence, the limited data solely on human MDSC and aging will be considered here.

A much-cited seminal paper (198) reported that the mean absolute numbers of peripheral blood cells with the PMN-MDSC phenotype CD11b⁺CD15⁺CD33⁺ HLA-DR⁻ were on average slightly but significantly higher in healthy older-vs-younger Canadians (61–76-vs-19–59 y.o.) but notably higher in frail seniors (67–99 y.o.), associated with higher levels of proinflammatory cytokines that may facilitate MDSC production. Hence, higher levels of cells with the phenotype of MDSC may primarily be associated with the degree of individual frailty and “inflammaging” (199). Other investigations on MDSC in human aging have suggested that very old Brazilians (80–100 y.o.) possess a higher percentage of circulating PMN-MDSC than 20–30 y.o. controls, but absolute numbers per ml of blood were not different in this case (200). However, suppressive capacity was not tested in either of these studies so the cells could not be confirmed as MDSC. As far as we are aware, there is a single paper addressing functionality, showing that bone marrow MDSC from older donors retain their suppressive functionality (76). These papers (196, 198, 200) with quite sparse data are constantly cited in support of the contention that MDSC increase with age in healthy humans, but the actual published evidence for this is not overwhelming. It is nonetheless highly likely that the commonly slightly enhanced systemic levels of inflammatory mediators seen in older humans, especially in frailty, coupled with the likely myeloid skewing of hematopoiesis contribute to higher levels of immunosuppression by MDSC in older adults as a further negative impact of “inflammaging,” also associated with poorer responses to vaccination. As we have argued before (201), there is still very little data on the numbers, types and functions of MDSC in older humans. However, the much larger datasets in the clinical context are consistent with their important role in healthy aging.

Impact of MDSC on vaccination

Perhaps surprisingly, there are few studies on the impact of MDSC on either prophylactic or therapeutic vaccination, but most of the available data suggest that MDSC reduce vaccine efficacy. Vaccination itself induces a local inflammatory reaction and MDSC. Surprisingly, multiple doses of SARS-CoV-2 vaccines do not induce MDSC (202), perhaps due to the unique lipid composition of the vaccines. In mice, BCG recruits immune suppressive M-MDSC that impair T cell priming in the draining lymph node (77). In Rhesus macaques immunized with an mRNA influenza vaccine, M-MDSC and PMN-MDSC invade the injection site but not the draining lymph nodes (78), suggesting that vaccine immune responsiveness may not always be affected. This possibility is supported by a study of South African infants up to one year of age that showed no correlation between MDSC levels and responsiveness to common childhood vaccines; however, the levels of MDSC were only <1% at 6 weeks of age and decreased thereafter (203). Elevated levels of MDSC that occur in diet-induced obese mice inhibit antibody production and T cell proliferation to a hepatitis B vaccine (79). MDSC play a unique role in HIV vaccines as shown in a mouse model using EcoHIV infection. Initial infection produces HIV-1 GAG-specific CD8⁺T cells that reduce virally infected cells. However, within seven days CD8⁺ T cells are rapidly reduced and PD-L1-expressing HIV-infected MDSC appear and persist (80), potentially reducing vaccine efficacy and duration of protection.

In disease-prevalent low- and middle-income countries, individuals in endemic areas of parasite infection may have infection-induced MDSC and vaccine design for use in such countries needs to consider MDSC immune suppressive activity regardless of vaccine target (81). Therefore, vaccine design against parasitic infection in these areas needs to consider MDSC immune suppressive activity. Indeed, in a mouse model of Chagas disease, depletion of MDSC enhanced the efficacy of an anti-T. cruzi vaccine (82).

Along similar lines, therapeutic vaccines for cancer (e.g. tumor peptides, recombinant viral vector vaccines, DC-based vaccines) must consider the presence of existing MDSC, given that MDSC impair DC function (204). In an ovarian cancer mouse model, a prime/boost vaccine strategy with an antigen-armed oncolytic virus combined with depletion of MDSC and PD-1 checkpoint blockade was most efficacious in restoring antitumor CD8⁺ T cell activity (83). Immunization with a viral vector-based cancer vaccine targeting a mouse HPV tumor similarly resulted in optimal activation of HPV E7-specific CD8⁺ T cells and maximal mouse survival when combined with Sunitinib to deplete MDSC (84). In a clinical trial of small cell lung cancer patients (NCT#00617409), 41.7% of patients given DC-transduced with wild-type p53 in combination with all trans retinoic acid to deplete MDSC developed p53-reactive CD8⁺ T cells compared to 20% of patients receiving only the vaccine (85).

Conclusions

The presence of MDSC in many diseases and non-pathological physiological conditions has made them an obvious target for intervention. In diseases where they are detrimental, strategies are being developed to eliminate them. In conditions where they are beneficial MDSC are being exploited as therapeutic agents. For example, in pregnancy, MDSC facilitate maternal-fetal tolerance and could be induced or adoptively transferred to enhance in vitro fertilization and successful pregnancies.

Where MDSC exhibit a dual protective/detrimental role it is unclear if they should be targeted. Their protective effects in reducing metabolic dysfunction in obesity are countered by their association with increased cancer risk. Likewise, MDSC provide protection against excessive inflammation during acute sepsis, but contribute to post-sepsis immune suppression. MDSC may also play a dual role in immunity to infections in that their anti-inflammatory activity prevents excessive inflammation while impairing cell-mediated immune mechanisms for clearing pathogens. The same situation accompanies normal aging where MDSC could temper inflammaging but at the cost of depressing immunity to infection. Similarly, the immune suppressive potency of MDSC makes them a prime cell for controlling GVHD in transplant patients and multiple mouse studies have shown that adoptive transfer of large quantities of MDSC can produce disease remission in autoimmune conditions. However, this strategy has the potential to increase the risk of infection in the recipients.

In pathologic situations such as cancer where MDSC are exclusively detrimental therapeutic strategies to eliminate them are already benefiting patients in clinical trials. However, for situations in which MDSC play a dual beneficial and detrimental role a comprehensive understanding of the quantity, timing, location, and specific phenotype of MDSC is needed to intervene specifically and effectively. Given the variation in pathologies and individuals efficacious intervention in the latter conditions is likely to require customization.

Abbreviations:

AlloHCT

allogeneic hematopoietic stem cell transplantation

Arg1

arginase 1

CMP

common myeloid progenitor

DC

dendritic cell(s)

DLN

draining lymph node(s)

GVHD

graft vs. host disease

MDSC

myeloid-derived suppressor cell(s)

M-MDSC

monocytic MDSC(s)

MOG

myelin oligodendrocyte glycoprotein

Mtb

Mycobacterium tuberculosis

NOS2

nitric oxide synthase 2 (also known as iNOS)

PGE2

prostaglandin E2

PMN-MDSC

polymorphonuclear or granulocytic MDSC(s)

ROS

reactive oxygen species

SLE

systemic lupus erythmatosis

Tregs

T regulatory cell(s)