Myeloid-derived suppressor cells in peripheral blood as predictive biomarkers in patients with solid tumors undergoing immune checkpoint therapy: systematic review and meta-analysis.

Background: Immunotherapeutic approaches, including immune checkpoint inhibitor (ICI) therapy, are increasingly recognized for their potential. Despite notable successes, patient responses to these treatments vary significantly. The absence of reliable predictive and prognostic biomarkers hampers the ability to foresee outcomes. This meta-analysis aims to evaluate the predictive significance of circulating myeloid-derived suppressor cells (MDSC) in patients with solid tumors undergoing ICI therapy, focusing on progression-free survival (PFS) and overall survival (OS). Methods: A comprehensive literature search was performed across PubMed and EMBASE from January 2007 to November 2023, utilizing keywords related to MDSC and ICI. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) directly from the publications or calculated them based on the reported data. A hazard ratio greater than 1 indicated a beneficial effect of low MDSC levels. We assessed heterogeneity and effect size through subgroup analyses. Results: Our search yielded 4,023 articles, of which 17 studies involving 1,035 patients were included. The analysis revealed that patients with lower levels of circulating MDSC experienced significantly improved OS (HR=2.13 [95% CI 1.51-2.99]) and PFS (HR=1.87 [95% CI 1.29-2.72]) in response to ICI therapy. Notably, heterogeneity across these outcomes was primarily attributed to differences in polymorphonuclear MDSC (PMN-MDSC) subpopulations and varying cutoff methodologies used in the studies. The monocytic MDSC (M-MDSC) subpopulation emerged as a consistent and significant prognostic marker across various subgroup analyses, including ethnicity, tumor type, ICI target, sample size, and cutoff methodology. Conclusions: Our findings suggest that standardized assessment of MDSC, particularly M-MDSC, should be integral to ICI therapy strategies. These cells hold the promise of identifying patients at risk of poor response to ICI therapy, enabling tailored treatment approaches. Further research focusing on the standardization of markers and validation of cutoff methods is crucial for integrating MDSC into clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023420095, identifier CRD42023420095.

PI3Kγ inhibition combined with DNA vaccination unleashes a B-cell-dependent antitumor immunity that hampers pancreatic cancer.

Phosphoinositide-3-kinase γ (PI3Kγ) plays a critical role in pancreatic ductal adenocarcinoma (PDA) by driving the recruitment of myeloid-derived suppressor cells (MDSC) into tumor tissues, leading to tumor growth and metastasis. MDSC also impair the efficacy of immunotherapy. In this study we verify the hypothesis that MDSC targeting, via PI3Kγ inhibition, synergizes with α-enolase (ENO1) DNA vaccination in counteracting tumor growth.Mice that received ENO1 vaccination followed by PI3Kγ inhibition had significantly smaller tumors compared to those treated with ENO1 alone or the control group, and correlated with i) increased circulating anti-ENO1 specific IgG and IFNγ secretion by T cells, ii) increased tumor infiltration of CD8+ T cells and M1-like macrophages, as well as up-modulation of T cell activation and M1-like related transcripts, iii) decreased infiltration of Treg FoxP3+ T cells, endothelial cells and pericytes, and down-modulation of the stromal compartment and T cell exhaustion gene transcription, iv) reduction of mature and neo-formed vessels, v) increased follicular helper T cell activation and vi) increased "antigen spreading", as many other tumor-associated antigens were recognized by IgG2c "cytotoxic" antibodies. PDA mouse models genetically devoid of PI3Kγ showed an increased survival and a pattern of transcripts in the tumor area similar to that of pharmacologically-inhibited PI3Kγ-proficient mice. Notably, tumor reduction was abrogated in ENO1 + PI3Kγ inhibition-treated mice in which B cells were depleted.These data highlight a novel role of PI3Kγ in B cell-dependent immunity, suggesting that PI3Kγ depletion strengthens the anti-tumor response elicited by the ENO1 DNA vaccine.

Harnessing Metformin's Immunomodulatory Effects on Immune Cells to Combat Breast Cancer.

Metformin, a medication known for its anti-glycemic properties, also demonstrates potent immune system activation. In our study, using a 4T1 breast cancer model in BALB/C WT mice, we examined metformin's impact on the functional phenotype of multiple immune cells, with a specific emphasis on natural killer T (NKT) cells due to their understudied role in this context. Metformin administration delayed the appearance and growth of carcinoma. Furthermore, metformin increased the percentage of IFN-γ+ NKT cells, and enhanced CD107a expression, as measured by MFI, while decreasing PD-1+, FoxP3+, and IL-10+ NKT cells in spleens of metformin-treated mice. In primary tumors, metformin increased the percentage of NKp46+ NKT cells and increased FasL expression, while lowering the percentages of FoxP3+, PD-1+, and IL-10-producing NKT cells and KLRG1 expression. Activation markers increased, and immunosuppressive markers declined in T cells from both the spleen and tumors. Furthermore, metformin decreased IL-10+ and FoxP3+ Tregs, along with Gr-1+ myeloid-derived suppressor cells (MDSCs) in spleens, and in tumor tissue, it decreased IL-10+ and FoxP3+ Tregs, Gr-1+, NF-κB+, and iNOS+ MDSCs, and iNOS+ dendritic cells (DCs), while increasing the DCs quantity. Additionally, increased expression levels of MIP1a, STAT4, and NFAT in splenocytes were found. These comprehensive findings illustrate metformin's broad immunomodulatory impact across a variety of immune cells, including stimulating NKT cells and T cells, while inhibiting Tregs and MDSCs. This dynamic modulation may potentiate its use in cancer immunotherapy, highlighting its potential to modulate the tumor microenvironment across a spectrum of immune cell types.

Guardians and Mediators of Metastasis: Exploring T Lymphocytes, Myeloid-Derived Suppressor Cells, and Tumor-Associated Macrophages in the Breast Cancer Microenvironment.

Breast cancers (BCs) are solid tumors composed of heterogeneous tissues consisting of cancer cells and an ever-changing tumor microenvironment (TME). The TME includes, among other non-cancer cell types, immune cells influencing the immune context of cancer tissues. In particular, the cross talk of immune cells and their interactions with cancer cells dramatically influence BC dissemination, immunoediting, and the outcomes of cancer therapies. Tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) represent prominent immune cell populations of breast TMEs, and they have important roles in cancer immunoescape and dissemination. Therefore, in this article we review the features of TILs, TAMs, and MDSCs in BCs. Moreover, we highlight the mechanisms by which these immune cells remodel the immune TME and lead to breast cancer metastasis.

Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Drug-Loaded Mesoporous Silica Nanoparticles Enhance Antitumor Immunotherapy by Regulating MDSCs.

Myeloid-derived suppressor cells (MDSCs) are recognized as major immune suppressor cells in the tumor microenvironment that may inhibit immune checkpoint blockade (ICB) therapy. Here, we developed a Stattic-loaded mesoporous silica nanoparticle (PEG-MSN-Stattic) delivery system to tumor sites to reduce the number of MDSCs in tumors. This approach is able to significantly deplete intratumoral MSDCs and thereby increase the infiltration of T lymphocytes in tumors to enhance ICB therapy. Our approach may provide a drug delivery strategy for regulating the tumor microenvironment and enhancing cancer immunotherapy efficacy.

Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis.

Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell-to-myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell-derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell-mediated mechanism that drives the development of MDSCs during tumor immune escape.

Eosinophils, basophils and myeloid-derived suppressor cells in chronic Loa loa infection and its treatment in an endemic setting.

BACKGROUND: Chronic infection by Loa loa remains an unsolved immunological paradox. Despite harboring subcutaneously migrating adult worms and often high densities of microfilariae, most patients experience only relatively mild symptoms, yet microfilaricidal treatment can trigger life-threatening inflammation. Here, we investigated innate cell populations hypothesized to play a role in these two faces of the disease, in an endemic population in Gabon. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed numbers and activation of eosinophils and basophils, as well as myeloid-derived suppressor cell (MDSC) subsets and associated circulating cytokine levels by flow cytometry in sex- and age-matched L. loa-uninfected (LL-), -amicrofilaraemic (MF-) and -microfilaraemic (MF+) individuals (n = 42), as well as microfilaraemic individuals treated with albendazole (n = 26). The percentage of eosinophils was lower in LL- (3.0%) than in the combined L. loa-infected population, but was similar in MF+ (13.1%) and MF- (12.3%). Upon treatment of MF+, eosinophilia increased from day 0 (17.2%) to day 14 (24.8%) and had decreased below baseline at day 168 (6.3%). Expression of the eosinophil activation marker CD123 followed the same pattern as the percentage of eosinophils, while the inverse was observed for CD193 and to some extent CD125. Circulating IL-5 levels after treatment followed the same pattern as eosinophil dynamics. Basophil numbers did not differ between infection states but increased after treatment of MF+. We did not observe differences in MDSC numbers between infection states or upon treatment. CONCLUSIONS/SIGNIFICANCE: We demonstrate that both chronic infection and treatment of L. loa microfilaraemia are associated with eosinophil circulation and distinct phenotypical activation markers that might contribute to inflammatory pathways in this setting. In this first ever investigation into MDSC in L. loa infection, we found no evidence for their increased presence in chronic loiasis, suggesting that immunomodulation by L. loa is induced through other pathways.

Natural Killer Cells Reprogram Myeloid-Derived Suppressor Cells to Induce TNF-α Release via NKG2D-Ligand Interaction after Cryo-Thermal Therapy.

In our previous studies, a novel cryothermal therapy (CTT) was developed to induce systemic long-term anti-tumor immunity. Natural killer (NK) cells were found to play an important role in CTT-induced long-term immune-mediated tumor control at the late stage after CTT, but the underlying mechanism is unclear. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that have potent immunosuppressive effects on T cells and weaken the long-term benefits of immunotherapy. Consequently, overcoming MDSC immunosuppression is essential for maintaining the long-term efficacy of immunotherapy. In this study, we revealed that NK cells considerably diminish MDSC accumulation at the late stage after CTT, boost T cell production, increase T cell activation, and promote MDSC maturation, culminating in Th1-dominant CD4+ T cell differentiation and enhancing NK and CD8+ T cell cytotoxicity. Additionally, NK cells activate ERK signaling in MDSCs through NKG2D-ligand interaction to increase the activity of tumor necrosis factor (TNF)-α converting enzyme (TACE)-cleaved membrane TNF-α. Furthermore, Increased TACE activity releases more soluble TNF-α from MDSCs to promote MDSC maturation. In our studies, we propose a novel mechanism by which NK cells can overcome MDSC-induced immunosuppression and maintain CTT-induced persistent anti-tumor immunity, providing a prospective therapeutic option to improve the performance of cancer immunotherapy.

Decidual natural killer cells dysfunction is caused by IDO downregulation in dMDSCs with Toxoplasma gondii infection.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in maintaining maternal-fetal tolerance by expressing some immune-suppressive molecules, such as indoleamine 2,3-dioxygenase (IDO). Toxoplasma gondii (T. gondii) infection can break the immune microenvironment of maternal-fetal interface, resulting in adverse pregnancy outcomes. However, whether T. gondii affects IDO expression in dMDSCs and the molecular mechanism of its effect are still unclear. Here we show, the mRNA level of IDO is increased but the protein level decreased in infected dMDSCs. Mechanistically, the upregulation of transcriptional levels of IDO in dMDSCs is regulated through STAT3/p52-RelB pathway and the decrease of IDO expression is due to its degradation caused by increased SOCS3 after T. gondii infection. In vivo, the adverse pregnancy outcomes of IDO-/- infected mice are more severe than those of wide-type infected mice and obviously improved after exogenous kynurenine treatment. Also, the reduction of IDO in dMDSCs induced by T. gondii infection results in the downregulation of TGF-ß and IL-10 expression in dNK cells regulated through Kyn/AhR/SP1 signal pathway, eventually leading to the dysfunction of dNK cells and contributing the occurrence of adverse pregnancy outcomes. This study reveals a novel molecular mechanism in adverse pregnancy outcome induced by T. gondii infection.

ß-Glucan Subverts the Function of Myeloid Cells in Neonates.

ß-Glucan is the main component of the cell wall of pathogen-associated molecular patterns (PAMPs) including various yeast, fungi, or certain bacteria. Previous reports demonstrated that ß-glucan was widely investigated as a potent immunomodulators to stimulate innate and adaptive immune responses, which indicated that it could be recommended as an effective adjuvant in immunotherapy. However, the detailed effects of ß-glucan on neonatal immunity are still largely unknown. Here, we found that ß-glucan did not affect the frequencies and numbers of myeloid cells in the spleen and bone marrow from neonates. Functional assay revealed that ß-glucan from neonates compromised the immunosuppressive function of immature myeloid cells, which were myeloid-derived suppressor cells (MDSCs). Flow cytometry or gene expression analysis revealed that ß-glucan-derived polymorphonuclear (PMN)-MDSCs produced lower level of reactive oxygen species (ROS) and arginase-1 (Arg1) in neonatal mice. Furthermore, ß-glucan administration significantly decreased the frequency and ROS level of PMN-MDSCs in vitro. These observations suggest that ß-glucan facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.

The post-septic peripheral myeloid compartment reveals unexpected diversity in myeloid-derived suppressor cells.

Introduction: Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. Methods: Cellular Indexing of Transcriptomes and Epitopes by Sequencing and transcriptomic analysis are used to describe MDSC subpopulations based on differential gene expression, RNA velocities, and biologic process clustering. Results: We identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome. Discussion: The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity.

Myeloid-derived suppressor cells in pleural effusion as a diagnostic marker for early discrimination of pulmonary tuberculosis from pneumonia.

Introduction: Tuberculous pleural effusion (TPE) stands as one of the primary forms of extrapulmonary tuberculosis (TB) and frequently manifests in regions with a high prevalence of TB, consequently being a notable cause of pleural effusion in such areas. However, the differentiation between TPE and parapneumonic pleural effusion (PPE) presents diagnostic complexities. This study aimed to evaluate the potential of myeloid-derived suppressor cells (MDSCs) in the pleural fluid as a potential diagnostic marker for distinguishing between TPE and PPE. Methods: Adult patients, aged 18 years or older, who presented to the emergency room of a tertiary referral hospital and received a first-time diagnosis of pleural effusion, were prospectively enrolled in the study. Various immune cell populations, including T cells, B cells, natural killer (NK) cells, and MDSCs, were analyzed in both pleural fluid and peripheral blood samples. Results: In pleural fluid, the frequency of lymphocytes, including T, B, and NK cells, was notably higher in TPE compared to PPE. Conversely, the frequency of polymorphonuclear (PMN)-MDSCs was significantly higher in PPE. Notably, compared to traditional markers such as the neutrophil-to-lymphocyte ratio and adenosine deaminase level, the frequency of PMN-MDSCs emerged as a more effective discriminator between PPE and TPE. PMN-MDSCs demonstrated superior positive and negative predictive values and exhibited a higher area under the curve in the receiver operating characteristic curve analysis. PMN-MDSCs in pleural effusion increased the levels of reactive oxygen species and suppressed the production of interferon-gamma from T cells following nonspecific stimulation. These findings suggest that MDSC-mediated immune suppression may contribute to the pathology of both TPE and PPE. Discussion: The frequency of PMN-MDSCs in pleural fluid is a clinically useful indicator for distinguishing between TPE and PPE.

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 ß-glucan treatment improves antitumor response by regulating myeloid-derived suppressor cells in triple-negative breast cancer.

Granular ß-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.

Hepatic recruitment of myeloid-derived suppressor cells upon liver injury promotes both liver regeneration and fibrosis.

BACKGROUND: The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury. METHODS: We established four liver injury models of mice including CCl4-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11b+Gr-1+) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-ß were measured by ELISA assay and followed by being blocked with specific antibodies. RESULTS: The intrahepatic infiltrations of MDSCs with surface marker of CD11b+Gr-1+ remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11b+Ly6G-Ly6Chigh) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-ß. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs). CONCLUSIONS: The dramatically and quickly infiltrated CD11b+Gr-1+ MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.

Targeting tumorous Circ-E-Cadherinencoded C-E-Cad inhibits the recruitment and function of breast cancer-associated myeloid-derived suppressor cells.

We previously demonstrated that the C-E-cad protein encoded by circ-E-cadherin promotes the self-renewal of glioma stem cells. The expression pattern of C-E-cad in breast cancer and its potential function in the tumor microenvironment are unclear. The expression of circ-E-cadherin and C-E-cad was detected in breast cancer specimens. The influence of C-E-cad expression on MDSCs was assessed using FACS and in vivo tumorigenesis experiments. The synergistic effect of anti-C-E-cad and anti-PD-1 antibodies was validated in vivo. circ-E-cadherin and the encoded protein C-E-cad were found to be upregulated in breast cancer vs. normal samples. C-E-cad promotes the recruitment of MDSCs, especially PMN-MDSCs. C-E-cad activates EGFR signaling in tumor cells and promotes the transcription of CXCL8; moreover, C-E-cad binds to MDSCs and maintains glycolysis in PMN-MDSCs. Targeting C-E-cad enhanced anti-PD-1 efficiency. Our data suggested that C-E-cad is markedly overexpressed in breast cancer and promotes MDSC recruitment and survival. Targeting C-E-cad increases the efficacy of immune checkpoint inhibitor therapy.

17ß-estradiol promotes myeloid-derived suppressor cells functions and alleviates inflammatory bowel disease by activation of Stat3 and NF-κB signalings.

Inflammatory bowel disease (IBD) describes a group of clinically common autoimmune diseases characterized by chronic intestinal inflammation, with gender differences in prevalence. Estrogen has been previously shown to exert anti-inflammatory action in IBD development, however, the mechanisms remain obscure. Recent research has revealed that myeloid-derived suppressor cells (MDSCs) play a protective role in IBD pathogenesis. To investigate the molecular mechanisms of estrogen steroid 17ß-estradiol (E2) in IBD progression, we established IBD mouse models (DNB-induced) with or without prior ovariectomy (OVX) and E2 implantation. We found that OVX led to worse IBD symptoms and reduced MDSCs frequency, whereas E2 significantly alleviated these effects in vivo. Moreover, in vitro experiments showed that E2 promoted the proliferation and immunosuppressive function of MDSCs through phosphorylation of Stat3 and p65. Mechanistically, E2-mediated Stat3/p65 phosphorylation depends on the interaction between HOTAIR, a long non-coding RNA that are well-known in MDSCs proliferation, and Stat3/p65 respectively. In conclusion, our study revealed that E2 promotes the expansion and immunosuppressive function of MDSCs, and thus diminished the occurrence and development of IBD.

Electrically activated polymetallic nanocrystals for long-term tumor suppression via oxygen-independent ROS generation and electro-immunotherapy.

The low oxidation level and immunosuppressive microenvironment within hypoxic tumor tissue are critical factors contributing to the inefficacy of various anti-tumor strategies. Herein, we have designed a novel intravenous injection nanoplatform to conduct electro-immunotherapy, based on phospholipid-modified PtPd nanocrystals loaded with the immunoregulator IPI549 (LP@Pt-Pd@IPI549 nanoparticles, LPPI). LPPI responds to reactive oxygen species (ROS), triggering a cascade of therapeutic effects that overcome hypoxia-related resistance and effectively eradicate hypoxic tumors. Firstly, under electric field exposure, LPPI relied on water rather than oxygen to generate abundant ROS under hypoxic conditions for tumor electrodynamic therapy (EDT). Moreover, the generated ROS further induced the disintegration of the outer phospholipid membrane of LPPI, leading to the release of the immunoregulator and inhibition of myeloid-derived suppressor cells (MDSCs), triggering cascade immune responses. Additionally, the immunomodulatory effects of IPI549, in synergy with the immunogenic cell death (ICD) induced by EDT, reversed the immunosuppressive microenvironment contributing to tumor resistance. In summary, EDT transiently killed tumor cells while simultaneously generating antigen release, instigating an adaptive immune response for electro-immunotherapy, resulting in a potent and long-lasting tumor inhibition effect.