Search Results (23)

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in cancer and represent one of the major drivers of tumor-associated immunosuppression. MDSCs actively contribute to tumor progression by inhibiting both innate and adaptive immune responses, promoting angiogenesis, metastatic dissemination, and resistance to immunotherapy. Two major subsets have been identified, polymorphonuclear (PMN-) and monocytic (Mo-) MDSCs, each characterized by distinct phenotypic, metabolic, and suppressive properties. Within the tumor microenvironment (TME), MDSCs establish a complex network of interactions with T-, B-, NK-cells, dendritic cells, and macrophages, thereby orchestrating immune escape and tumor persistence. Recent evidence highlights the pivotal role of metabolic rewiring in regulating MDSC survival and suppressive activity. Enhanced aerobic glycolysis, fatty acid oxidation, amino acid depletion, reactive oxygen species (ROS) production, and adenosine metabolism collectively sustain MDSC-mediated immune dysfunction and shape the immunosuppressive TME. In particular, the crosstalk between PMN-MDSCs and NK cells has emerged as a critical mechanism of tumor immune evasion, leading to impaired NK cell cytotoxicity, altered activating receptor expression, and defective cytokine production. In this review, we summarize the current knowledge on the phenotypic and functional heterogeneity of MDSCs, their metabolic adaptations, and their interactions with immune effector populations in cancer. Furthermore, we discuss emerging therapeutic strategies aimed at targeting MDSC recruitment, differentiation, metabolic pathways, and suppressive functions. Understanding the molecular and metabolic mechanisms governing MDSC biology may provide novel opportunities to overcome tumor-induced immunosuppression and improve the efficacy of current cancer immunotherapies. Full article

Bone metastasis remains a major cause of morbidity in advanced cancer, driven not only by tumor–bone crosstalk but also by profound immune remodeling within the marrow. Myeloid-derived suppressor cells (MDSCs), including polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subsets, are increasingly recognized as central effectors of this process, integrating inflammatory signals with metabolic and stromal cues to enforce immune suppression and support skeletal colonization. In this review, we synthesize current evidence that bone metastases transform the bone marrow into an “MDSC amplifier,” where vascular and endosteal niches, CXCL12-rich stromal compartments, hypoxia, and adipocyte-derived lipids collectively promote MDSC recruitment, persistence, and functional maturation. We discuss the dominant suppressive programs deployed by MDSCs in bone (e.g., arginase-1 activity, reactive oxygen/nitrogen species, and checkpoint ligand expression), and how these mechanisms converge to impair cytotoxic T-cell and NK-cell responses while fostering regulatory T-cell dominance. Importantly, because the marrow is a hematopoietic organ, bone lesions can also generate systemic consequences through myeloid spillover, providing a mechanistic basis for reduced responsiveness to immune checkpoint blockade in bone-dominant disease. We then evaluate pharmacologic strategies to target MDSCs in the context of bone metastasis, including approaches that block trafficking (e.g., CCR2/CXCR2 axes), deplete or reprogram suppressive myeloid states (e.g., STAT3-directed strategies, differentiation therapy), and disrupt bone-resorptive feedback loops (e.g., receptor activator of NF-κB ligand (RANKL) inhibition and bisphosphonates), emphasizing rational combinations and sequencing to limit marrow toxicity. Finally, we highlight emerging single-cell and spatial profiling tools that can resolve bone-specific heterogeneity in MDSCs and guide biomarker-driven, mechanism-informed therapeutic development. Full article

It is broadly realized that the body’s metabolism has a profound impact on tumor progression. However, pathophysiological mechanisms underlying the metabolic modulation of the tumor immune microenvironment remain incompletely understood. Here, we report that long-chain fatty acids (LCFAs) can directly modulate the function of myeloid-derived suppressor cells (MDSCs), a central component of establishing the tumor immune microenvironment. In vitro or in vivo exposure to LCFAs significantly reduces the expression levels of signature immunosuppressive genes of both monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). As a result, mice fed with a diet of high LCFA content exhibit delayed tumor progression and prolonged survival in different cancer models. Furthermore, this LCFA-mediated inhibition of M-MDSCs and PMN-MDSCs correlates with enhanced CD8⁺ T antitumor immunity, which is abolished in tumor-bearing nude mice. These results have revealed a previously under-recognized role of LCFAs in the tumor immune microenvironment, implicating novel therapeutic strategies for cancer treatment. Full article

Background/Objectives: Colorectal cancer (CRC) remains a major global health challenge and current therapies are not always effective. In addition, certain immune cell populations, such as myeloid-derived suppressor cells (MDSCs), pose a significant barrier to immune-based treatments. Some phytochemicals, particularly compounds derived from Allium spp. like Propyl-Propane Thiosulfonate (PTSO), have shown strong immunomodulatory potential in digestive disorders. This study aims to investigate the capacity of PTSO to modulate immune responses and affect tumor progression in CRC models, in vitro and in vivo, with a focus on the immune cell populations that comprise the tumor microenvironment. Methods: Human peripheral blood mononuclear cells (hPBMCs) were incubated with PTSO (25 μM for 48 h) and characterized by flow cytometry. These cells (1 × 10⁶) were then injected into NOD scid gamma (NSG) immunodeficient mice, which were simultaneously induced to develop a subcutaneous tumor by injection of HCT116 enriched cancer stem cells (CSCs) colonospheres (60,000 cells/mouse). Results: PTSO reduced MDSC populations, specifically, it significantly reduced monocytic (M-MDSCs, Control: 7.27 ± 0.53% vs. PTSO: 4.70 ± 2.39%; p = 0.0458) and polymorphonuclear (PMN-MDSCs, Control: 5.28 ± 0.99% vs. PTSO: 3.41 ± 1.58%; p = 0.0385) MDSCs. In parallel, PTSO increased T cell subpopulations, particularly interferon gamma (IFNG)-producing cytotoxic CD8⁺ T cells (Control: 9.52 ± 2.06% vs. PTSO: 15.04 ± 5.01%; p = 0.0685). In the humanized tumor xenograft mouse, the administration of PTSO-pretreated hPBMCs led to a significant reduction in tumor size (Control: 1.43 ± 0.82 cm³ vs. PTSO: 0.44 ± 0.35 cm³; p = 0.0068), accompanied by increased infiltration of CD4⁺ T lymphocytes and Natural Killer (NK) cells and downregulation of immunosuppressive genes. These effects resulted in a reduction in cancer cell proliferation and invasiveness. Conclusions: The dual effect of PTSO on immune cell populations, reducing immunosuppressive myeloid cells and enhancing effector T lymphocyte and NK cell responses, resulted in an anti-tumor effect, highlighting this bioactive compound as a promising adjuvant in CRC immunotherapy and opening avenues for future research combining immunotherapy with PTSO in alternative models to optimize dosing and enhance translational potential. Full article

Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system to investigate how HNSCC cells affect tumor-associated myeloid cells. We found that the presence of cancer cells significantly enhances myeloid cell proliferation and promotes TAM differentiation. To identify potential therapeutic agents, we screened a custom library of 70 kinase inhibitors to assess their effects on distinct subsets of tumor-associated myeloid cells. We discovered specific inhibitors that differentially suppressed the populations of TAMs, monocytic MDSCs (M-MDSCs), or polymorphonuclear MDSCs (PMN-MDSCs), suggesting that inhibiting different targets could reduce distinct subsets of tumor-associated myeloid cells. Conversely, some inhibitors were found to increase the population of CD11b⁺Ly6G⁻Ly6C⁻ myeloid cells. Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction. Full article

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by a chronic inflammatory state that plays a relevant role in the disease pathogenesis (as proven by high levels of inflammatory cytokines with prognostic significance and by a persistent oxidative stress) and by extensive neoangiogenesis in bone marrow (BM) and spleen. Myeloid-derived suppressor cells (MDSCs) are immature cells that expand in patients with cancer, sepsis or chronic inflammation, favoring tumor onset and progression mainly through the decrease in immune surveillance and the promotion of neoangiogenesis. In this paper, we evaluated the presence of circulating MDSCs in PMF patients, the plasmatic factors involved in their mobilization/expansion and the correlations with laboratory, genetic and clinical parameters. The data indicated that MDSCs could have a relevant role in PMF as a new pathogenic mechanism contributing to explaining the phenotypic diversity observed during the clinical course of the disease, or a potential new target for personalized treatment. Full article

Myeloid-derived suppressor cells (MDSCs) play an essential role in suppressing the antitumor activity of T lymphocytes in solid tumors, thus representing an attractive therapeutic target to enhance the efficacy of immunotherapy. However, the differences in protein expression between MDSCs and their physiological counterparts, particularly polymorphonuclear neutrophils (PMNs), remain inadequately characterized, making the specific identification and targeting of MDSCs difficult. PMNs and PMN-MDSCs share markers such as CD11b+CD14−CD15+/CD66b+, and some MDSC-enriched markers are emerging, such as LOX-1 and CD84. More proteomics studies are needed to identify the signature and markers for MDSCs. Recently, we reported the induced differentiation of isogenic PMNs or MDSCs (referred to as iPMNs and iMDSCs, respectively) from the human promyelocytic cell line HL60. Here, we profiled the global proteomics and membrane proteomics of these cells with quantitative mass spectrometry, which identified a 41-protein signature (“cluster 6”) that was upregulated in iMDSCs compared with HL60 and iPMN. We further integrated our cell line-based proteomics data with a published proteomics dataset of normal human primary monocytes and monocyte-derived MDSCs induced by cancer-associated fibroblasts. The analysis identified a 38-protein signature that exhibits an upregulated expression pattern in MDSCs compared with normal monocytes or PMNs. These signatures may provide a hypothesis-generating platform to identify protein biomarkers that phenotypically distinguish MDSCs from their healthy counterparts, as well as potential therapeutic targets that impair MDSCs without harming normal myeloid cells. Full article

Patients admitted to the intensive care unit (ICU) often experience endotoxemia, nosocomial infections and sepsis. Polymorphonuclear and monocytic myeloid-derived suppressor cells (PMN-MDSCs and M-MDSCs) can have an important impact on the development of infectious diseases, but little is known about their potential predictive value in critically ill patients. Here, we used unsupervised flow cytometry analyses to quantify MDSC-like cells in healthy subjects challenged with endotoxin and in critically ill patients admitted to intensive care units and at risk of developing infections. Cells phenotypically similar to PMN-MDSCs and M-MDSCs increased after endotoxin challenge. Similar cells were elevated in patients at ICU admission and normalized at ICU discharge. A subpopulation of M-MDSC-like cells expressing intermediate levels of CD15 (CD15^int M-MDSCs) was associated with overall mortality (p = 0.02). Interestingly, the high abundance of PMN-MDSCs and CD15^int M-MDSCs was a good predictor of mortality (p = 0.0046 and 0.014), with area under the ROC curve for mortality of 0.70 (95% CI = 0.4–1.0) and 0.86 (0.62–1.0), respectively. Overall, our observations support the idea that MDSCs represent biomarkers for sepsis and that flow cytometry monitoring of MDSCs may be used to risk-stratify ICU patients for targeted therapy. Full article

Myeloid-derived suppressor cells (MDSCs) are key determinants of the immunosuppressive microenvironment in tumors. As ion channels play key roles in the physiology/pathophysiology of immune cells, we aimed at studying the ion channel repertoire in tumor-derived polymorphonuclear (PMN-MDSC) and monocytic (Mo-MDSC) MDSCs. Subcutaneous tumors in mice were induced by the Lewis lung carcinoma cell line (LLC). The presence of PMN-MDSC (CD11b⁺/Ly6G⁺) and Mo-MDSCs (CD11b⁺/Ly6C⁺) in the tumor tissue was confirmed using immunofluorescence microscopy and cells were identified as CD11b⁺/Ly6G⁺ PMN-MDSCs and CD11b⁺/Ly6C⁺/F4/80⁻/MHCII⁻ Mo-MDSCs using flow cytometry and sorting. The majority of the myeloid cells infiltrating the LLC tumors were PMN-MDSC (~60%) as compared to ~10% being Mo-MDSCs. We showed that PMN- and Mo-MDSCs express the Hv1 H⁺ channel both at the mRNA and at the protein level and that the biophysical and pharmacological properties of the whole-cell currents recapitulate the hallmarks of Hv1 currents: ~40 mV shift in the activation threshold of the current per unit change in the extracellular pH, high H⁺ selectivity, and sensitivity to the Hv1 inhibitor ClGBI. As MDSCs exert immunosuppression mainly by producing reactive oxygen species which is coupled to Hv1-mediated H⁺ currents, Hv1 might be an attractive target for inhibition of MDSCs in tumors. Full article

Myeloid-derived suppressor cells MDSCs are a heterogeneous population of cells that expand beyond their physiological regulation during pathologies such as cancer, inflammation, bacterial, and viral infections. Their key feature is their remarkable ability to suppress T cell and natural killer NK cell responses. Certain risk factors for severe COVID-19 disease, such as obesity and diabetes, are associated with oxidative stress. The resulting inflammation and oxidative stress can negatively impact the host. Similarly, cancer cells exhibit a sustained increase in intrinsic ROS generation that maintains the oncogenic phenotype and drives tumor progression. By disrupting endoplasmic reticulum calcium channels, intracellular ROS accumulation can disrupt protein folding and ultimately lead to proteostasis failure. In cancer and COVID-19, MDSCs consist of the same two subtypes (PMN-MSDC and M-MDSC). While the main role of polymorphonuclear MDSCs is to dampen the response of T cells and NK killer cells, they also produce reactive oxygen species ROS and reactive nitrogen species RNS. We here review the origin of MDSCs, their expansion mechanisms, and their suppressive functions in the context of cancer and COVID-19 associated with the presence of superoxide anion ^•O₂⁻ and reactive oxygen species ROS. Full article

Bacillus Calmette-Guérin (BCG) instillations for the treatment of non-muscle-invasive bladder cancer patients can result in significant side effects and treatment failure. Immune checkpoint blockade and/or decreasing tumor-infiltrating myeloid suppressor cells may be alternative or complementary treatments. Here, we have characterized immune cell infiltration and chemoattractant molecules in mouse orthotopic MB49 bladder tumors. Our data show a 100-fold increase in CD45⁺ immune cells from day 5 to day 9 tumors including T cells and mainly myeloid cells. Both monocytic myeloid-derived suppressor-cells (M-MDSC) and polymorphonuclear (PMN)-MDSC were strongly increased in day 9 tumors, with PMN-MDSC representing ca. 70% of the myeloid cells in day 12 tumors, while tumor associated macrophages (TAM) were only modestly increased. The kinetic of PD-L1 tumor expression correlated with published data from patients with PD-L1 expressing bladder tumors and with efficacy of anti-PD-1 treatment, further validating the orthotopic MB49 bladder-tumor model as suitable for designing novel therapeutic strategies. Comparison of chemoattractants expression during MB49 bladder tumors grow highlighted CCL8 and CCL12 (CCR2-ligands), CCL9 and CCL6 (CCR-1-ligands), CXCL2 and CXCL5 (CXCR2-ligands), CXCL12 (CXCR4-ligand) and antagonist of C5/C5a as potential targets to decrease myeloid suppressive cells. Data obtained with a single CCR2 inhibitor however showed that the complex chemokine crosstalk would require targeting multiple chemokines for anti-tumor efficacy. Full article

Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of Irf8 leads to massive accumulation of CD11b⁺Gr1⁺ immature myeloid cells (IMCs), particularly the CD11b⁺Ly6C^hi/+Ly6G⁻ polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs). Under pathological conditions such as cancer, Irf8 is silenced by its promoter DNA hypermethylation, resulting in accumulation of PMN-MDSCs and CD11b⁺ Ly6G⁺Ly6C^lo monocytic MDSCs (M-MDSCs) in mice. IRF8 is often silenced in MDSCs in human cancer patients. MDSCs are heterogeneous populations of immune suppressive cells that suppress T and NK cell activity to promote tumor immune evasion and produce growth factors to exert direct tumor-promoting activity. Emerging experimental data reveals that IRF8 is also expressed in non-hematopoietic cells. Epithelial cell-expressed IRF8 regulates apoptosis and represses Osteopontin (OPN). Human tumor cells may use the IRF8 promoter DNA methylation as a mechanism to repress IRF8 expression to advance cancer through acquiring apoptosis resistance and OPN up-regulation. Elevated OPN engages CD44 to suppress T cell activation and promote tumor cell stemness to advance cancer. IRF8 thus is a transcription factor that regulates both the immune and non-immune components in human health and diseases. Full article

Breast cancer is the most common cancer in women worldwide, and lung metastasis is one of the most frequent distant metastases. When breast cancer metastasizes to the lung, group 2 innate lymphoid cells (ILC2s) are thought to promote tumor growth via the activation of myeloid-derived suppressor cells (MDSCs), which are known to negatively regulate anticancer immune responses. However, it remains to be elucidated exactly how this ILC2–MDSC interaction is involved in tumor growth during metastases formation. Using a 4T1/LM4 breast cancer mouse model, we found that ILC2s were activated in both the micro- and macrometastatic regions, suggesting sustained activation throughout the metastatic cascades via IL-33/ST2 signaling. Consistent with IL-13 secretion from activated ILC2s, the frequencies of polymorphonuclear (PMN)- and monocytic (M)-MDSCs were also significantly elevated during the progression from micro- to macrometastatic cancer. However, the effects of ILC2-induced MDSC functionality on the microenvironment differed in a metastatic-stage-specific manner. Our findings indicate that ILC2s may induce the immunosuppressive functions of MDSCs during the later stages of metastasis. Concomitantly, ILC2 may instigate extracellular matrix remodeling by PMN-MDSC activation during the early stages of metastasis. These metastatic-stage-specific changes may contribute to metastatic tumor growth in the microenvironment of breast cancer lung metastasis. Full article

Propolis is a natural product produced by bees that is primarily used in complementary and alternative medicine and has anti-inflammatory, antibacterial, antiviral, and antitumoral biological properties. Some studies have reported the beneficial effects of propolis in models of allergic asthma. In a previous study, our group showed that green propolis treatment reduced airway inflammation and mucus secretion in an ovalbumin (OVA)-induced asthma model and resulted in increased regulatory T cells (Treg) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) frequencies in the lungs, two leukocyte populations that have immunosuppressive functions. In this study, we evaluated the anti-inflammatory effects of artepillin C (ArtC), the major compound of green propolis, in the context of allergic airway inflammation. Our results show that ArtC induces in vitro differentiation of Treg cells and monocytic MDSC (M-MDSC). Furthermore, in an OVA-induced asthma model, ArtC treatment reduced pulmonary inflammation, eosinophil influx to the airways, mucus and IL-5 secretion along with increased frequency of M-MDSC, but not Treg cells, in the lungs. Using an adoptive transfer model, we confirmed that the effect of ArtC in the reduction in airway inflammation was dependent on M-MDSC. Altogether, our data show that ArtC exhibits an anti-inflammatory effect and might be an adjuvant therapy for allergic asthma. Full article

Polymorphonuclear neutrophils (PMNs) are traditionally regarded as professional phagocytic and acute inflammatory cells that engulf the microbial pathogens. However, accumulating data have suggested that PMNs are multi-potential cells exhibiting many important biological functions in addition to phagocytosis. These newly found novel activities of PMN include production of different kinds of cytokines/chemokines/growth factors, release of neutrophil extracellular traps (NET)/ectosomes/exosomes and trogocytosis (membrane exchange) with neighboring cells for modulating innate, and adaptive immune responses. Besides, PMNs exhibit potential heterogeneity and plasticity in involving antibody-dependent cellular cytotoxicity (ADCC), cancer immunity, autoimmunity, inflammatory rheumatic diseases, and cardiovascular diseases. Interestingly, PMNs may also play a role in ameliorating inflammatory reaction and wound healing by a subset of PMN myeloid-derived suppressor cells (PMN-MDSC). Furthermore, PMNs can interact with other non-immune cells including platelets, epithelial and endothelial cells to link hemostasis, mucosal inflammation, and atherogenesis. The release of low-density granulocytes (LDG) from bone marrow initiates systemic autoimmune reaction in systemic lupus erythematosus (SLE). In clinical application, identification of certain PMN phenotypes may become prognostic factors for severe traumatic patients. In the present review, we will discuss these newly discovered biological and pathobiological functions of the PMNs. Full article