Differentiation Of Myeloid-derived Suppressor Cells Research Articles

Platinum(IV) Complexes Trigger Death Receptors and Natural Killer Cells to Suppress Breast Cancer.

Chemoimmunotherapy is an alternative treatment against cancers. Platinum(IV) complexes FMP and DFMP, coupling formononetin derivative as axial ligand(s), were designed to suppress triple-negative breast cancer (TNBC) by activating death receptors (DRs) and natural killer (NK) cells. These complexes show great potential to overcome the resistance of TNBC to chemotherapy by inducing both intrinsic and extrinsic apoptosis in cancer cells. Particularly, FMP with one axial formononetin derivative not only induced the caspase-3-dependent intrinsic apoptosis but also upregulated the expression of DRs and caspase-8, triggered the extrinsic apoptosis, and enhanced the cytotoxic ability of NK92 cells. Moreover, FMP increased the release of granzyme B, restrained the proliferation and differentiation of myeloid-derived suppressor cells, and the secretion of IL-10, thus inhibiting the TNBC in vitro and in vivo. The results demonstrate that FMP overcomes the chemoresistance and immune escape of TNBC through a new mechanism involving the synergy of chemotherapy and immunotherapy.

Stimulator of Interferon Genes Signal in Lung Cancer Regulates Differentiation of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment Via the Interferon Regulatory Factor 3/NF-κB Pathway.

Background: This study was designed to explore the action mechanism of stimulator of interferon genes (STING) on the differentiation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment of lung cancer. Methods: Bioinformatics analysis yielded a potential pathway for STING to regulate MDSC differentiation, the interferon regulatory factor 3 (IRF3)/NF-κB axis. The transfection efficiency of STING overexpression plasmid and small interfering RNA against IRF3 (siIRF3) was examined by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection, A9 cells were co-cultured with extracted bone marrow cells (BMCs). MDSC differentiation, protein expression of the IRF3/NF-κB pathway, and changes in nuclear translocation of NF-κB were analyzed by flow cytometry, Western blot, and immunofluorescence staining experiments. A transplanted tumor mouse model was used for invivo experiments. After cyclic diadenyl monophosphate (CDA; STING agonist) treatment, changes in MDSC differentiation and protein expression of the IRF3/NF-κB axis in transplanted tumors were verified by immunohistochemical staining, qRT-PCR, and Western blot. Results: Coculture of A9 cells and BMCs promoted MDSC differentiation, inhibited activation of IRF3/NF-κB signal in A9 cells, and boosted nuclear translocation of NF-κB. However, after the upregulation of STING, IRF3/NF-κB signal was activated, while MDSC differentiation and nuclear translocation of NF-κB were inhibited. SiIRF3 reversed the effects of STING overexpression. In vivo, CDA dampened MDSC differentiation and promoted protein expression of the IRF3/NF-κB axis. Conclusion: STING signal in lung cancer cells inhibits MDSC differentiation through activation of the IRF3/NF-κB pathway.

20(S)-ginsenoside Rg3 alleviates DSS-induced colitis by promoting ERK-dependent maturation of MDSCs into M2 macrophages.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunosuppressive functions that play various roles in tumors and inflammatory diseases. In colitis, MDSCs accumulate in the inflamed colon, where they mature into M2-polarized macrophages and modulate inflammatory responses. Ginsenosides, active components of ginseng, have been shown to display colitis-alleviating effects in mouse models. However, the detailed mechanisms underlying these effects are incompletely understood. This study explores the impact of ginsenosides on MDSC functions and differentiation, focusing on their potential to mitigate inflammatory symptoms in colitis. Among the 15 ginsenosides tested, Rg3(R) and Rg3(S) were found to promote the maturation of MDSCs into M2 macrophages at non-cytotoxic concentrations. This was confirmed by the increased expression of ARG1, an immunosuppressive marker. These effects were attributed to the activation of the ERK pathway, as confirmed by selective ERK inhibition. In a DSS-induced colitis mouse model, oral administration of Rg3(S) alleviated disease severity and increased MDSC differentiation into M2 macrophages in colon lamina propria, highlighting its therapeutic potential colitis.

Tumor cell-derived N-acetyl-aspartyl-glutamate reshapes the tumor microenvironment to facilitate breast cancer metastasis.

Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity. N-acetyl-aspartyl-glutamate (NAAG) has been extensively studied in neurological disorders; however, its potential role in restricting anti-tumor immunity has not been investigated. Here, we demonstrated that NAAG or its synthetase RimK-like family member B (RIMKLB) significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which in turn promoted breast cancer growth and metastasis. Mechanistically, NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor (NR2B-NMDAR)-dependent p38-NOTCH1 axis, and subsequently stimulating tumor cell migration and invasion, as well as inducing PMN-MDSC differentiation and expansion. In mouse models, RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression. An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients. Collectively, our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer.

Lactate: a rising star in tumors and inflammation.

Lactate has been traditionally regarded as a mere byproduct of glycolysis or metabolic waste. However, an increasing body of literature suggests its critical role in regulating various physiological and pathological processes. Lactate is generally associated with hypoxia, inflammation, viral infections, and tumors. It performs complex physiological roles by activating monocarboxylate transporter (MCT) or the G protein-coupled receptor GPR81 across the cell membrane. Lactate exerts immunosuppressive effects by regulating the functions of various immune cells (such as natural killer cells, T cells, dendritic cells, and monocytes) and its role in macrophage polarization and myeloid-derived suppressor cell (MDSC) differentiation in the tumor microenvironment. Lactic acid has also recently been found to increase the density of CD8+ T cells, thereby enhancing the antitumor immune response. Acute or chronic inflammatory diseases have opposite immune states in the inflammatory disease microenvironment. Factors such as cell types, transcriptional regulators, ionic mediators, and the microenvironment all contribute to the diverse functions lactate exhibits. Herein, we reviewed the pleiotropic effects of lactate on the regulation of various functions of immune cells in the tumor microenvironment and under inflammatory conditions, which may help to provide new insights and potential targets for the diagnosis and treatment of inflammatory diseases and malignancies.

Platelet-activating factor: a potential therapeutic target to improve cancer immunotherapy.

The tumor microenvironment (TME) fosters cancer progression by supporting the differentiation and proliferation of myeloid-derived suppressor cells (MDSCs), which play a critical role in suppressing immune responses and facilitating tumor growth. Recent findings by Dahal etal. reveal that platelet-activating factor (PAF), a lipid mediator elevated in the TME, contributes to the differentiation of neutrophils into immunosuppressive neutrophils. They showed that inhibiting PAF signaling reduces MDSC-mediated immunosuppression, thereby enhancing cytotoxic T-cell activity. This approach may improve cancer immunotherapy outcomes, particularly when combined with checkpoint blockade therapies, suggesting a promising avenue for therapeutic development.

IMMU-58. BCAT1 TARGETED METABOLIC REPROGRAMMING PLAYS CRITICAL ROLES IN MODULATING MYELOID DERIVED SUPPRESSOR CELL FUNCTION IN GLIOBLASTOMA

Abstract A key component that has limited the efficacy of immunotherapy in glioblastoma (GBM) is the significant infiltration of immunosuppressive myeloid cells. Our previous work characterized myeloid derived suppressor cells (MDSCs) unique to GBM that drive tumor growth and immune suppression. Transcriptomic and flow cytometric analyses demonstrated that the most induced programs in these MDSCs are dominated by metabolic and mTOR pathways. Therefore, we aimed to understand the role of metabolic reprogramming in MDSC differentiation and immunosuppressive function. Using single cell RNA sequencing, we identified overexpression of enzymes and transporters involved in branched-chain amino acid (BCAA) metabolism, notably branched chain aminotransferase 1 (BCAT1), the first enzyme in the metabolic pathway. Intriguingly, this was only found in specific populations of early and monocytic MDSCs (E-MDSCs, M-MDSCs), and not polymorphonuclear MDSCs (PMN-MDSCs). Using established MDSC modeling systems, we found that M-MDSC differentiation and T cell suppressive function are dependent on BCAAs and can be hindered by pharmacological inhibition of BCAT1 activity or genetic knockout of BCAT1. We also establish that the influence of BCAA on M-MDSC function is specifically reliant on the BCAT1-mediated step of BCAA metabolism. To determine the underlying mechanism driving BCAT1’s impact on M-MDSC function, we evaluated the activity of signaling pathways known to be critical to M-MDSCs including the mTORC1 pathway. We found that the impact of BCAA and BCAT1 activity on M-MDSC function is abrogated by inhibition of mTORC1 pathway with reduction in M-MDSC differentiation and activity. Consistent with our single cell RNA sequencing analysis, modulation of BCAA levels and BCAT1 activity had no impact on PMN-MDSCs. Our results underscore the critical role of BCAT1 in preferentially modulating M-MDSC activity through mTORC1 signaling. Our finding paves the way for discovery of a targetable therapeutic approach to harness immunometabolism in myeloid cells to develop novel immune therapies.

IMMU-57. METHYL-B-CYCLODEXTRIN PARTIALLY REVERSES THE IMMUNOSUPPRESSIVE EFFECTS OF GLIOBLASTOMA DERIVED EXTRACELLULAR VESICLES ON LYMPHOCYTES

Abstract Extracellular vesicles (EVs) derived from glioblastoma (GBM) have been demonstrated in multiple studies to contribute to tumorigenesis, invasion, and immunosuppression. Our prior results demonstrate that EVs can induce the differentiation of myeloid-derived suppressor cells (MDSCs), which in turn impair T cell activation and proliferation in vitro. Methyl-B-Cyclodextrin (MBCD), a cholesterol depleting agent, can interfere with lipid rafts, which are cholesterol rich microdomains on the cellular membrane that act as a docking mechanism for EV uptake. Herein we demonstrate that MBCD can inhibit EV uptake and partially reverse the immunosuppressive effects of EVs on both monocytes and T cells. METHODS EVs were isolated using stepwise ultracentrifugation from GBM cultures. GBM derived EVs were then added to extracted monocytes from donor samples with or without MBCD for 72 hours under hypoxic conditions. The EV exposed monocytes were then co-cultured with T lymphocytes and cell proliferation was measured via flow cytometry. RESULTS Exposure to GBM-derived EVs induced MDSC differentiation in monocytes by at least 50% while the addition of MBCD reduced MDSC levels similar to that of the control group. Moreover, MBCD exposure resulted in increased T cell proliferation in the presence of EV treated monocytes compared to untreated samples. CONCLUSION MBCD can be used as a therapeutic agent to reverse MDSC induction by GBM derived EVs and can partially rescue T cell activation and proliferation.

Platelet-activating factor (PAF) promotes immunosuppressive neutrophil differentiation within tumors

Chronic inflammatory milieu in the tumor microenvironment (TME) leads to the recruitment and differentiation of myeloid-derived suppressor cells (MDSCs). Polymorphonuclear (PMN)-MDSCs, which are phenotypically and morphologically defined as a subset of neutrophils, cause major immune suppression in the TME, posing a significant challenge in the development of effective immunotherapies. Despite recent advances in our understanding of PMN-MDSC functions, the mechanism that gives rise to immunosuppressive neutrophils within the TME remains elusive. Both in vivo and in vitro, newly recruited neutrophils into the tumor sites remained activated and highly motile for several days and developed immunosuppressive phenotypes, as indicated by increased arginase 1 (Arg1) and dcTrail-R1 expression and suppressed anticancer CD8 T cell cytotoxicity. The strong suppressive function was successfully recapitulated by incubating naive neutrophils with cancer cell culture supernatant in vitro. Cancer metabolite secretome analyses of the culture supernatant revealed that both murine and human cancers released lipid mediators to induce the differentiation of immunosuppressive neutrophils. Liquid chromatography-mass spectrometry (LC-MS) lipidomic analysis identified platelet-activation factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) as a common tumor-derived lipid mediator that induces neutrophil differentiation. Lysophosphatidylcholine acyltransferase 2 (LPCAT2), the PAF biosynthetic enzyme, is up-regulated in human pancreatic ductal adenocarcinoma (PDAC) and shows an unfavorable correlation with patient survival across multiple cancer types. Our study identifies PAF as a lipid-driven mechanism of MDSC differentiation in the TME, providing a potential target for cancer immunotherapy.

VEGFA contributes to tumor property of glioblastoma cells by promoting differentiation of myeloid-derived suppressor cells

BackgroundGlioblastoma (GBM) is a malignant astrocytic tumor and its progression involves the regulation of vascular endothelial growth factor-A (VEGFA). However, the mechanism of VEGFA in regulating GBM progression remains unclear.MethodsVEGFA mRNA expression was analyzed by quantitative real-time polymerase chain reaction. Protein expression of VEGFA, cluster of differentiation 9 (CD9), CD81, and transforming growth factor-β1 (TGF-β1) was detected by western blotting assay. Flow cytometry assay was conducted to assess cell proliferation, cell apoptosis and myeloid-derived suppressor cell (MDSC) differentiation. TUNEL cell apoptosis detection kit was utilized to analyze cell apoptosis of tumors. Angiogenic capacity was investigated by tube formation assay. Transwell assay was used to assess cell migration and invasion. The effect of VEGFA on tumor formation was determined by a xenograft mouse model assay. Immunohistochemistry assay was used to analyze positive expression rate of VEGFA in tumor tissues. TGF-β1 level was detected by enzyme-linked immunosorbent assay.ResultsVEGFA expression was upregulated in GBM tissues, GBM cells, and exosomes from GBM patients and GBM cells. VEGFA silencing led to decreased cell proliferation, tube formation, migration and invasion and increased cell apoptosis. Moreover, VEGFA knockdown also delayed tumor formation. VEGFA promoted MDSC differentiation and TGF-β1 secretion by MDSCs by being packaged into exosomes. In addition, TGF-β1 knockdown displayed similar effects with VEGFA silencing on GBM cell phenotypes, and MDSCs attenuated VEGFA knockdown-induced effects by secreting TGF-β1 in A172 and U251 cells.ConclusionVEGFA contributed to tumor property of GBM cells by promoting MDSC differentiation and TGF-β1 secretion by MDSCs, providing potential targets for GBM treatment.

Bexarotene Induce Differentiation of Myeloid-Derived Suppressor Cells through Arg-1 Signalling Pathway

BackgroundCellular therapy has emerged as a promising strategy to minimize the use of conventional immunosuppressive drugs and ultimately induce long-term graft survival. Myeloid-derived suppressor cells (MDSCs) can be used for immunosuppressive treatment of solid organ transplants. MethodsGranular macrophage colony-stimulating factor (GM-CSF) and bexarotene, an X receptor-selective retinoid, were used for in vitro MDSC induction. Cell phenotypes were detected using flow cytometry, while mRNA was detected via real-time PCR. A mouse skin transplantation model was used to verify the inhibitory effects of this treatment. ResultsThe combination of GM-CSF and bexarotene-induced MDSC differentiation. MDSCs induce immune tolerance by inhibiting T-cell proliferation, influencing cytokine secretion, and inducing T-cell transformation into Treg cells. Combination treatment significantly up-regulated Arg-1 expression in MDSCs. The Arg-1 inhibitor nor-NOHA neutralized the immunosuppressive activity of MDSCs, suggesting the involvement of Arg-1 in MDSC-mediated immunosuppression. GM-CSF and bexarotene-induced MDSCs prolong graft survival in mouse skin transplants, exhibiting in vivo immunosuppressive effects. ConclusionsA new method for inducing MDSCs is presented. The combination of GM-CSF and bexarotene induces MDSCs with remarkable regulatory functions. Adoptive transfer of the induced MDSCs extended allograft survival. These results suggest that MDSCs can potentially be used in future clinical transplants to inhibit rejection, reduce adverse events, and induce operative tolerance.

Myeloid‑derived suppressor cells as targets of emerging therapies and nanotherapies (Review).

Breast cancer (BC) is the leading cause of cancer-related mortality among women worldwide. Immunotherapies are a promising approach in cancer treatment, particularly for aggressive forms of BC with high mortality rates. However, the current eligibility for immunotherapy remains limited to a limited fraction of patients with BC. Myeloid-derived suppressor cells (MDSCs), originating from myeloid cells, are known for their dual role in immunosuppression and tumor promotion, significantly affecting patient outcomes by fostering the formation of premetastatic niches. Consequently, targeting MDSCs has emerged as a promising avenue for further exploration in therapeutic interventions. Leveraging nanotechnology-based drug delivery systems, which excel in accumulating drugs within tumors via passive or active targeting mechanisms, are a promising strategy for the use of MDSCs in the treatment of BC. The present review discusses the immunosuppressive functions of MDSCs, their role in BC, and the diverse strategies for targeting them in cancer therapy. Additionally, the present review discusses future advancements in BC treatments focusing on MDSCs. Furthermore, it elucidates the mechanisms underlying MDSC activation, recruitment and differentiation in BC progression, highlighting the clinical characteristics that render MDSCs suitable candidates for the therapy and targeted nanotherapy of BC.

Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.

Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.

Engineered CD147-Deficient THP-1 Impairs Monocytic Myeloid-Derived Suppressor Cell Differentiation but Maintains Antibody-Dependent Cellular Phagocytosis Function for Jurkat T-ALL Cells with Humanized Anti-CD147 Antibody.

CD147 is upregulated in cancers, including aggressive T-ALL. Traditional treatments for T-ALL often entail severe side effects and the risk of relapse, highlighting the need for more efficacious therapies. ADCP contributes to the antitumor response by enhancing the ability of phagocytic cells to engulf cancer cells upon antibody binding. We aimed to engineer CD147KO THP-1 cells and evaluated their differentiation properties compared to the wild type. A humanized anti-CD147 antibody, HuM6-1B9, was also constructed for investing the phagocytic function of CD147KO THP-1 cells mediated by HuM6-1B9 in the phagocytosis of Jurkat T cells. The CD147KO THP-1 was generated by CRISPR/Cas9 and maintained polarization profiles. HuM6-1B9 was produced in CHO-K1 cells and effectively bound to CD147 with high binding affinity (KD: 2.05 ± 0.30 × 10-9 M). Additionally, HuM6-1B9 enhanced the phagocytosis of Jurkat T cells by CD147KO THP-1-derived LPS-activated macrophages (M-LPS), without self-ADCP. The formation of THP-1-derived mMDSC was limited in CD147KO THP-1 cells, highlighting the significant impact of CD147 deletion. Maintaining expression markers and phagocytic function in CD147KO THP-1 macrophages supports future engineering and the application of induced pluripotent stem cell-derived macrophages. The combination of HuM6-1B9 and CD147KO monocyte-derived macrophages holds promise as an alternative strategy for T-ALL.

Hyperexpression of tumor necrosis factor receptor 2 inhibits differentiation of myeloid-derived suppressor cells by instigating apolarity during ageing.

During the ageing process, TNF-α can promote the expansion of myeloid-derived suppressor cells (MDSCs). However, it remains unclear which receptor(s) of TNF-α are involved in and how they modulate this process. Here, we report that TNFR2 hyperexpression induced by either TNF-α or IL-6, two proinflammatory factors of senescence-associated secretory phenotype (SASP), causes cellular apolarity and differentiation inhibition in aged MDSCs. Ex vivo overexpression of TNFR2 in young MDSCs inhibited their polarity and differentiation, whereas in vivo depletion of Tnfr2 in aged MDSCs promotes their differentiation. Consequently, the age-dependent increase of TNFR2 versus unaltered TNFR1 expression in aged MDSCs significantly shifts the balance of TNF-α signaling toward the TNFR2-JNK axis, which accounts for JNK-induced impairment of cell polarity and differentiation failure of aged MDSCs. Consistently, inhibiting JNK attenuates apolarity and partially restores the differentiation capacity of aged MDSCs, suggesting that upregulated TNFR2/JNK signaling is a key factor limiting MDSC differentiation during organismal ageing. Therefore, abnormal hyperexpression of TNFR2 represents a general mechanism by which extrinsic SASP signals disrupt intrinsic cell polarity behavior, thereby arresting mature differentiation of MDSCs with ageing, suggesting that TNFR2 could be a potential therapeutic target for intervention of ageing through rejuvenation of aged MDSCs.

A phase 2 study of ipatasertib in combination with pembrolizumab for first-line treatment of recurrent or metastatic squamous cell cancer of the head and neck.

TPS6117 Background: Single agent pembrolizumab in relapsed / metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an estimated ORR of 19% and median OS of 13.6 months. There are several factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase 2 trial is designed to compare progression-free survival (PFS) in first line R/M, HNSCC patients treated with the combination ipatasertib and pembrolizumab versus pembrolizumab monotherapy treatment. Methods: In this open-label randomized phase 2 multicenter trial, patients with R/M HNSCC are treated with pembrolizumab 200mg on day 1 +/- ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ³ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with ipatasertib plus pembrolizumab compared to pembrolizumab alone using the Cox Model where randomized treatment assignment is the only variable in the model. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Ultimately, a total of 48 patients will be enrolled, with 24 patients in each cohort. To date, a total of 22 patients have been enrolled from 15 sites. Accrual is ongoing (NCT05172258). Clinical trial information: NCT05172258 .

Decitabine suppresses MDSC-induced immunosuppression through dual functional mechanism and inhibits melanoma metastasis.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting melanoma metastasis. Reprogramming MDSCs into mature M1 macrophages has emerged as a strategy to inhibit metastasis. Decitabine (Dec) is known to eradicate MDSCs and suppress tumor growth. In this study, we provide evidence that Dec not only reduces the MDSC population by inducing apoptosis, arresting cell cycle, and impairing recruitment, but also suppresses their immunosuppressive function by downregulating related genes and facilitating differentiation into M1 macrophages. Transcriptomic analysis of Dec-treated MDSCs revealed a marked downregulation of immunosuppressive genes including S100a9, S100a8, Vegf, Cxcr2, and Nos2. Meanwhile, M1 macrophage-associated genes involved in immune activation were upregulated, such as Ddx58, Isg15, Tap1, Ccl5, Cxcl9, and Cxcl10. Further bioinformatic analysis indicated that Dec promotes MDSC-to-M1 macrophage differentiation and activates innate immune pathways including NOD-like signaling to enhance anti-tumor immunity. Time-course studies implied that Dec upregulates myeloid transcription factor Irf7 to initiate MDSC differentiation and orchestrate the anti-tumor immune response. Collectively, our study unveils a novel dual-functional mechanism of Dec as both a cytotoxic agent reducing MDSCs and an inducer of their differentiation into M1 macrophages, thereby alleviating immunosuppression. This highlights Dec's potential for clinical melanoma metastasis suppression.

Ganoderma lucidum spores-derived particulate β-glucan treatment improves antitumor response by regulating myeloid-derived suppressor cells in triple-negative breast cancer

Granular β-1,3-glucan extracted from the wall of Ganoderma lucidum spores, named GPG, is a bioregulator. In this study, we investigated the structural, thermal, and other physical properties of GPG. We determined whether GPG ameliorated immunosuppression caused by Gemcitabine (GEM) chemotherapy. Triple-negative breast cancer mice with GPG combined with GEM treatment had reduced tumor burdens. In addition, GEM treatment alone altered the tumor microenvironment(TME), including a reduction in antitumor T cells and a rise in myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). However, combined GPG treatment reversed the tumor immunosuppressive microenvironment induced by GEM. GPG inhibited bone marrow (BM)-derived MDSC differentiation and reversed MDSC expansion induced by conditioned medium (CM) in GEM-treated E0771 cells through a Dectin-1 pathway. In addition, GPG downgraded PD-L1 and IDO1 expression on MDSC while boosting MHC-II, CD86, TNF-α, and IL-6 expression. In conclusion, this study demonstrated that GPG could alleviate the adverse effects induced by GEM chemotherapy by regulating TME.

Protein Signature Differentiating Neutrophils and Myeloid-Derived Suppressor Cells Determined Using a Human Isogenic Cell Line Model and Protein Profiling.

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.

Listeria-vectored cervical cancer vaccine candidate strains reduce MDSCs via the JAK-STAT signaling pathway.

Immunosuppressive status is prevalent in cancer patients and increases the complexity of tumor immunotherapy. It has been found that Listeria-vectored tumor vaccines had the potential ability of two-side regulatory effect on the immune response during immunotherapy. The results show that the combined immunotherapy with the LM∆E6E7 and LI∆E6E7, the two cervical cancer vaccine candidate strains constructed by our lab, improves the antitumor immune response and inhibits the suppressive immune response in tumor-bearing mice in vivo, confirming the two-sided regulatory ability of the immune response caused by Listeria-vectored tumor vaccines. The immunotherapy reduces the expression level of myeloid-derived suppressor cells (MDSCs)-inducing factors and then inhibits the phosphorylation level of STAT3 protein, the regulatory factor of MDSCs differentiation, to reduce the MDSCs formation ability. Moreover, vaccines reduce the expression of functional molecules associated with MDSCs may by inhibiting the phosphorylation level of the JAK1-STAT1 and JAK2-STAT3 pathways in tumor tissues to attenuate the immunosuppressive function of MDSCs. Immunotherapy with Listeria-vectored cervical cancer vaccines significantly reduces the level and function of MDSCs in vivo, which is the key point to the destruction of immunosuppression. The study for the first to elucidate the mechanism of breaking the immunosuppression.