Encyclopedia
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Brian SM Munansangu.
The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions.
- MDSC
- tuberculosis
- metabolic reprogramming
1. MDSC Classification
1.1. Origin and Identification
Myeloid-derived suppressor cells (MDSC) originate in the bone marrow during the development of myeloid progenitor cells, i.e., monocytes and neutrophils [20][1]. MDSC are divided into two major populations in both humans and mice, namely, polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC), as described previously in humans [21,22][2][3] and mice [23,24][4][5]. Recently, the markers lectin-type oxidized LDL receptor 1 (LOX1) [25][6] and fatty acid transporter 2 (FATP2) [26][7] have been shown to discriminate MDSC in tumor biology, although these have not yet been confirmed to be expressed by MDSC in infectious diseases such as active TB disease. Although M-MDSC and PMN-MDSC are considered the two main subsets of this suppressive population, recent evidence from human studies points towards a precursor subset termed early-stage MDSC [27][8]. Agrawal et al. also described a subverted DC phenotype characterized by low expression of MHC class II and CD80, and expression of CD14 that lacked CD1a molecule with the presence of CD83 and CD86 [28][9]. Additionally, our research group has also shown that CD14+ MDSC produces IL-10 and Il-6 with low levels of HLA-DR and CD80 [28,29][9][10]. Another recently described subset of MDSC has been termed eosinophilic (Eo)-MDSC and was identified in a mouse model infected with Staphylococcus aureus [30][11].
1.2. Recruitment and Expansion of MDSC
MDSC are recruited from the bone marrow in response to a variety of growth factors, hormones, and transcription factors, along with antigens linked to these pro-inflammatory conditions, thereby regulating myelopoiesis and inducing MDSC expansion. This process is enhanced by alarmins such as prostaglandin E2 (PGE2) and high mobility box group 1 (HMGB1) secreted by host tissues [31[12][13],32], and pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, IL-13, and S100A8/A9 [33][14]. Hypoxia and nutrient starvation may also affect the epigenetic status of myeloid cells [34][15], which is critical to the accumulation and reprogramming of MDSC in response to inflammatory or pathogenic insults [35][16]. Additionally, chemokines such as CCL2 (MCP-1, monocyte chemoattractant protein-1), CXCL2 (MIP-2, macrophage inflammatory protein 2), and CXCL8 have been identified to be vital in MDSC migration [36,37][17][18].
1.3. Immunosuppressive Mechanisms of MDSC
Although MDSC are widely considered regulators of the immune response, contributing to the homeostatic balance between pro- and anti-inflammatory responses, under aberrant conditions of chronic infection, MDSC are mainly considered detrimental to efficient host control of the pathogen. Several studies have shown how metabolic alterations, as well as those induced by infections, can influence the function, reprogramming, and differentiation of MDSC [38][19]. The mechanisms by which these cells suppress the immune response include:
- (i)
- (ii)
(ii) The production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by MDSC skews the polarization of monocytes, T cells, and macrophages towards anti-inflammatory and regulatory phenotypes [43,44][24][25];
- (iii)
(iii) Indirect suppression of T and effector B cells through the induction of tolerogenic immune cells such as de novo generation of Fox-P3+ regulatory T cells (Tregs) [45][26], regulatory B cells, and tumor-associated macrophages (TAMs) [41,46][22][27]. Recently, a novel mechanism was elucidated through which MDSC-dependent metabolic and functional paralysis of CD8+ T cells occurs [47][28]. The mechanism involves methylglyoxal-derived glycation of L-arginine products such as argpyrimidine and hydroimidazolone, thereby depleting cytosolic amino acids such as L-arginine, resulting in T-cell paralysis [47,48][28][29]. The transfer of methylglyoxal from MDSC to T cells is dependent on cell-–cell contact, resulting in more T-cell suppression at sites where MDSC may accumulate, such as tumor tissue [47][28];
- (iv)
(iv) Secretion of suppressive cytokines such as TGF-β and IL-10 that exert direct suppressive effects on T-cell responses [45][26];
- (v)
(v) Induction of T-cell apoptosis through the induction of the B7 family of immune-regulatory ligands, a co-signaling network superfamily that plays an essential role in the modification of T-cell activation and tolerance [49][30], such as B7-H1 (programmed cell death ligand 1 (PD-L1)), B7-H3, and B7-H4 [50][31], and impairment of T-cell migration through the reduction of CD62L expression [29][10].
For the past ~10 years, most immunosuppressive mechanisms have been elucidated from cellular interactions within the tumor microenvironment (TME), driving inferences for MDSC immunosuppressive functions in other conditions.
2. Immunometabolism of MDSC in Oncology
Metabolic dysregulation is a hallmark of numerous cancer types [107][32]. Altered metabolism has been observed in aggressive tumors such as glioblastoma (GBM) and ovarian and gastric cancer. MDSC have been shown to sense or exhibit plasticity in their environment and respond by selecting the most efficient metabolic pathways to sustain their suppressive and pro-tumorigenic functions [108][33]. In the TME, MDSC increase uptake of FA and activate the switch from glycolysis to FAO [109][34].2.1. Metabolic Reprogramming of MDSC
As previously noted, MDSC exhibit distinct functions and phenotypes in various disease settings [42][23]. They display a certain degree of plasticity where they can assume a pro- or anti-inflammatory phenotype to support tumor proliferation [110][35]. Although the underlying mechanism leading to MDSC function and activation in TB is not fully known, metabolic reprogramming of MDSC underpins many of the suppressive functions in cancer [42][23]. As with cancer cells, available evidence indicates that MDSC can undergo anaerobic glycolysis and OXPHOS, which are influenced by substrate availability and by signaling pathways elicited by metabolites or pathogen-derived inflammatory signals [42,111][23][36]. During maturation, MDSC exhibit elevated utilization of central carbon metabolism, the PPP, glycolysis, and the TCA cycle [112][37]. Various signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)–serine threonine protein kinase (AKT)–mTOR pathway, operate in concert to control metabolic reprogramming/activity in immune cells [113][38]. Under conditions of oxygen deprivation, mTOR signaling stimulates the HIF-1α pathway, resulting in upregulation of glycolytic enzymes, glucose, and lactate transporters—all of which result in the Warburg effect [47][28]. The phenotypic heterogeneity of MDSC could cause MDSC to compete with other immune cells for carbon acquisition in the TME and fall under the control of energy metabolic pathways, such as FA metabolism [114][39], which has a direct effect on the regulation of OXPHOS and glycolysis [114][39]. Furthermore, the TME may dysregulate some key genes associated with hallmark cancer pathways [115[40][41],116], such as HIF-1α (de-regulating cellular energetics), telomerase activation (enabling replicative immortality) [116][41], and activation of the NF-κβ and TGF-β pathways (antagonizing growth suppressor activity of p53 pathways) [117][42]. The pulmonary granuloma from M. tb infection may similarly dysregulate some key genes as seen in cancer. HIF-1α binds to the promoter of lactate dehydrogenase A (LDHA), which catalyzes the conversion of pyruvate to lactate, and in some cancers, isoforms of LDHA subunits have the highest efficiency of converting pyruvate to lactate and are linked to increased HIF-1α and VEGF expression, increased tumor size, enhanced metastatic potential, and a poor prognosis [22,118,119][3][43][44]. Non-host immune response therapies such as radiation therapy have also been associated with activation of MDSC and were dependent on enhanced lactate secretion and mediated by HIF-1α activity, resulting in the lactate-regulating MDSC function to reprogram the TME into a more immunosuppressive phenotype [120][45]. LDH has been found in active pulmonary TB patients’ bronchoalveolar lavage (BAL) fluid at high levels, and BAL LDH corresponds with increased serum LDH (Emad and Rezaian, 1999). Sputum-positive TB patients had higher serum levels of LDH1, LDH2, and LDH3, which have four, three, or two B subunits, respectively [121][46]. Increases in cerebrospinal fluid (CSF) lactate has also been linked to increased severity of tuberculous meningitis clinical stage [122][47]. This suggests that LDH levels and isoform specificity, as well as lactate levels, might be used as diagnostic or prognostic markers for pulmonary tuberculosis.
