Effect Of Myeloid-derived Suppressor Cells Research Articles

Study on the mechanism of MDSC-platelets and their role in the breast cancer microenvironment.

Myeloid-derived suppressor cells (MDSCs) are key immunosuppressive cells in the tumor microenvironment (TME) that play critical roles in promoting tumor growth and metastasis. Tumor-associated platelets (TAPs) help cancer cells evade the immune system and promote metastasis. In this paper, we describe the interaction between MDSCs and TAPs, including their generation, secretion, activation, and recruitment, as well as the effects of MDSCs and platelets on the generation and changes in the immune, metabolic, and angiogenic breast cancer (BC) microenvironments. In addition, we summarize preclinical and clinical studies, traditional Chinese medicine (TCM) therapeutic approaches, and new technologies related to targeting and preventing MDSCs from interacting with TAPs to modulate the BC TME, discuss the potential mechanisms, and provide perspectives for future development. The therapeutic strategies discussed in this review may have implications in promoting the normalization of the BC TME, reducing primary tumor growth and distant lung metastasis, and improving the efficiency of anti-tumor therapy, thereby improving the overall survival (OS) and progression-free survival (PFS) of patients. However, despite the significant advances in understanding these mechanisms and therapeutic strategies, the complexity and heterogeneity of MDSCs and side effects of antiplatelet agents remain challenging. This requires further investigation in future prospective cohort studies.

S100A8/A9-alarmin promotes local myeloid-derived suppressor cell activation restricting severe autoimmune arthritis

Immune-suppressive effects of myeloid-derived suppressor cells (MDSCs) are well characterized during anti-tumor immunity. The complex mechanisms promoting MDSC development and their regulatory effects during autoimmune diseases are less understood. We demonstrate that the endogenous alarmin S100A8/A9 reprograms myeloid cells to a Tcell suppressing phenotype during autoimmune arthritis. Treatment of myeloid precursors with S100-alarmins during differentiation induces MDSCs in a Toll-like receptor 4-dependent manner. Consequently, knockout of S100A8/A9 aggravates disease activity in collagen-induced arthritis due to a deficit of MDSCs in local lymph nodes, which could be corrected by adoptive transfer of S100-induced MDSCs. Blockade of MDSC function invivo aggravates disease severity in arthritis. Therapeutic application of S100A8 induces MDSCs invivo and suppresses the inflammatory phenotype of S100A9ko mice. Accordingly, the interplay of Tcell-mediated autoimmunity with a defective innate immune regulation is crucial for autoimmune arthritis, which should be considered for future innovative therapeutic options.

Myeloid-derived Suppressor Cells Activate Liver Natural Killer Cells in a Murine Model in Uveal Melanoma.

Elevated myeloid-derived suppressor cells (MDSCs) in many malignancies are associated with the increased risk for metastases and poor prognosis. Therefore, a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases. In this study, murine B16LS melanoma cells were transplanted into the posterior compartment (PC) of the eye of C57BL/6 mice. Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation, examined by flow cytometry for their expression of Gr1, CD11b, F4/80, RAE-1, and Mult-1, and further isolated for MDSCs and natural killer (NK) cells. The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma (IFN-γ) by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay. The impact of IFN-γ on liver metastases was examined via selectively depleting IFN-γ in vivo. The results showed that mice with liver metastases had increased levels of CD11b+Gr1+F4/80+ as well as CD11b+Gr1+F4/80- MDSCs. MDSCs significantly enhanced the generation of IFN-γ together with the cytotoxicity of the NK cells. Furthermore, these effects were cell-cell contact-dependent. Although IFN-γ was not of a toxic nature to the melanoma cells, it profoundly inhibited B16LS cell proliferation. Depleting IFN-γ in vivo led to increased liver metastases. All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response. Thus, the MDSCs' performance in different tumor models would need more investigation to boost current immunotherapy modalities.

Sildenafil, a Type-5 Phosphodiesterase Inhibitor, Fails to Reverse Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression in Cells Isolated From Tuberculosis Patients.

Successful TB treatment is hampered by increasing resistance to the two most effective first-line anti-TB drugs, namely isoniazid and rifampicin, thus innovative therapies focused on host processes, termed host-directed therapies (HDTs), are promising novel approaches for increasing treatment efficacy without inducing drug resistance. We assessed the ability of Sildenafil, a type-5 phosphodiesterase inhibitor, as a repurposed compound, to serve as HDT target, by counteracting the suppressive effects of myeloid-derived suppressor cells (MDSC) obtained from active TB cases on T-cell responsiveness. We confirm that MDSC suppress non-specific T-cell activation. We also show that Sildenafil treatment fails to reverse the MDSC-mediated suppression of T-cell functions measured here, namely activation and proliferation. The impact of Sildenafil treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.

Myeloid-derived suppressor cells cross-talk with B10 cells by BAFF/BAFF-R pathway to promote immunosuppression in cervical cancer

Immunosuppression induced by myeloid-derived suppressor cells (MDSCs) is one of the main obstacles to the efficacy of immunotherapy for cervical cancer. Recent studies on the immunosuppressive ability of MDSCs have primarily focused on T cells, but the effect of MDSCs on B cells function is still unclear. In a study of clinical specimens, we found that the accumulation of MDSCs in patients with cervical cancer was accompanied by high expression of B cell activating factor (BAFF) on the surface and high expression of interleukin (IL)-10-producing B cells (B10) in vivo. We found that the absence of BAFF could significantly inhibit tumor growth in a cervical cancer model using BAFF KO mice. Further studies showed that abundant MDSCs in cervical cancer induced B cells to differentiate into B10 cells by regulating BAFF which acted on the BAFF receptor (BAFF-R) of them. In this process, we found that a large amount of IL-10 secreted by B10 cells can activate STAT3 signaling pathway in MDSCs, and then form a positive feedback loop to promote the differentiation of B10 cells. Therefore, this study reveals a new mechanism of BAFF-mediated mutual immune regulation between MDSCs and B cells in the occurrence and development of cervical cancer.

The dual role of glioma exosomal microRNAs: glioma eliminates tumor suppressor miR-1298-5p via exosomes to promote immunosuppressive effects of MDSCs

Clear evidence shows that tumors could secrete microRNAs (miRNAs) via exosomes to modulate the tumor microenvironment (TME). However, the mechanisms sorting specific miRNAs into exosomes are still unclear. In order to study the biological function and characterization of exosomal miRNAs, we performed whole-transcriptome sequencing in 59 patients’ whole-course cerebrospinal fluid (CSF) small extracellular vesicles (sEV) and matched glioma tissue samples. The results demonstrate that miRNAs could be divided into exosome-enriched miRNAs (ExomiRNAs) and intracellular-retained miRNAs (CLmiRNAs), and exosome-enriched miRNAs generally play a dual role. Among them, miR-1298-5p was enriched in CSF exosomes and suppressed glioma progression in vitro and vivo experiments. Interestingly, exosomal miR-1298-5p could promote the immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) to facilitate glioma. Therefore, we found miR-1298-5p had different effects on glioma cells and MDSCs. Mechanically, downstream signaling pathway analyses showed that miR-1298-5p plays distinct roles in glioma cells and MDSCs via targeting SETD7 and MSH2, respectively. Moreover, reverse verification was performed on the intracellular-retained miRNA miR-9-5p. Thus, we confirmed that tumor-suppressive miRNAs in glioma cells could be eliminated through exosomes and target tumor-associated immune cells to induce tumor-promoting phenotypes. Glioma could get double benefit from it. These findings uncover the mechanisms that glioma selectively sorts miRNAs into exosomes and modulates tumor immunity.

Monocytic Myeloid-Derived Suppressor Cells Inhibit Myofibroblastic Differentiation in Mesenchymal Stem Cells Through IL-15 Secretion.

Background: Accumulating evidence indicates that mesenchymal stem cells (MSCs) are precursors of myofibroblasts, which play a vital role in renal fibrosis. The close interaction between MSCs and other immune cells regulates the development of multiple fibrosis-related diseases. However, the effect of myeloid-derived suppressor cells (MDSCs) on MSCs remains unexplored. Here, we investigated the effect of MDSCs on the myofibroblastic differentiation of MSCs. Methods: MSCs were induced to undergo myofibroblastic differentiation with transforming growth factor beta 1 (TGF-β1). M-MDSCs and G-MDSCs were sorted by flow cytometry. Supernatants derived from MDSCs were administered to cultured bone marrow MSCs (BM-MSCs) undergoing TGF-β1-induced myofibroblastic differentiation. Myofibroblastic differentiation was evaluated by immunostaining. The expression of fibrosis-related genes was determined by quantitative PCR and western blot analysis. In vitro, M-MDSC supernatant or M-MDSC supernatant with interleukin (IL)-15 mAbs was administered following unilateral renal ischemia-reperfusion injury (IRI) to observe the myofibroblast differentiation of renal resident MSCs (RRMSCs) in a murine model. Results: Myofibroblastic differentiation of MSCs was hindered when the cells were treated with MDSC-derived supernatants, especially that from M-MDSCs. The inhibitory effect of M-MDSC supernatant on the myofibroblastic differentiation of MSCs was partially mediated by IL-15-Ras-Erk1/2-Smad2/3 signaling. Treatment with M-MDSC supernatant ameliorated renal fibrosis and myofibroblastic differentiation in RRMSCs through IL-15. Additionally, M-MDSC supernatant increased M-MDSC infiltration in the kidney in a mouse IRI model. M-MDSC supernatant downregulated the adhesion and migration marker CD44 on the cell membrane of MSCs via IL-15. Conclusion: M-MDSC-derived supernatant inhibited the TGF-β1-induced myofibroblastic differentiation of MSCs through IL-15. Our findings shed new light on the effect of MDSCs on myofibroblastic differentiation and adhesion of MSCs, which might provide a new perspective in the development of treatment strategies for renal fibrosis.

Abstract P072: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) foster myeloid-derived suppressor cell-mediated tumor immune evasion in cholangiocarcinoma

Abstract Background and Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is predominantly expressed on immune cells. Although TRAIL biology has garnered considerable interest as a potential anti-cancer strategy, TRAIL agonists have had very limited anti-cancer activity in humans. TRAIL signaling in T cells may also potentially provide an immune checkpoint function as it can inhibit T cell activation and proliferation by interfering with T cell receptor signaling. However, this potential immune checkpoint function of TRAIL has not been examined in cancer biology. Cholangiocarcinoma (CCA), a highly lethal biliary tract cancer, provides a model to examine the potential immune checkpoint function of TRAIL. Methods: Using a syngeneic, orthotopic murine model of CCA (PMID: 29464042), murine CCA cells (SB cells) that express both TRAIL and TRAIL receptor (TR) were implanted into livers of WT and Tr−/− mice. Hence, in this model the host immune cells express TRAIL but not the receptor; therefore, they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed, and tumors were characterized using flow cytometry. Results: We observed that Tr−/− mice had a significant reduction in tumor burden compared to WT mice. Moreover, tumor bearing Tr−/− mice had a significant increase in cytotoxic T lymphocytes (CTLs) and enhanced CTL effector function. However, coculture of T cells with SB cells or SB cells deficient in Tr (SB-Tr−/−) did not result in a significant difference in T cell apoptosis or function, implying that TRAIL-TR is not a direct T cell checkpoint. Myeloid derived suppressor cells (MDSCs) were significantly decreased in Tr−/− tumors compared to WT tumors. Furthermore, implantation of SB cells devoid of Trail (SB-Trail−/−) into WT mice resulted in a significant reduction in tumor burden and MDSC infiltration. Coculture of SB cells with MDSCs from Tr−/− mice attenuated MDSC proliferation and immunosuppression compared to WT MDSCs. Moreover, treatment of MDSCs from Tr−/− mice with TRAIL recombinant protein resulted in a reduction in their proliferation and immunosuppressive function compare to MDSCs from WT mice implying that TRAIL-TR fosters MDSC growth and immunosuppressive function. In conclusion, we have demonstrated that Tr−/− mice have a significant reduction in CCA tumor burden and MDSC infiltration. Consequently, Tr−/− mice bearing tumors have enhanced CTL infiltration and function. These data suggest that the TRAIL-TR system mediates tumor immune evasion via MDSCs. Herein, we suggest that TRAIL-TR appears to function as an indirect T cell checkpoint by augmenting the immunosuppressive effects of MDSCs. Citation Format: Emilien Loeuillard, Juan Wang, Jingchun Yang, Haidong Dong, Gregory Gores, Sumera Ilyas. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) foster myeloid-derived suppressor cell-mediated tumor immune evasion in cholangiocarcinoma [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P072.

Granulocytic Myeloid-Derived Suppressor Cells in Murine Models of Immune-Mediated Bone Marrow Failure

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells with immunoregulatory function. Limited published studies have reported conflicting data concerning the effects of MDSCs on autoimmune diseases and graft-versus-host disease. MDSCs can be divided into two major subsets, more abundant granulocytic (G-MDSCs) and monocytic (M-MDSCs). We examined G-MDSCs in murine models of human bone marrow failure (BMF).We first characterized bone marrow (BM) MDSCs from C.B10 mice. CD11b +Ly6G +Ly6C low G-MDSCs suppressed in vitro proliferation of both CD4 and CD8 T cells from C57BL/6 (B6) mice, while Ly6G +Ly6C - cells had no effect and Ly6G -Ly6C + cells increased T cell proliferation (Fig. 1A). We then tested G-MDSCs in vivo utilizing antibody-mediated cell depletion. Lymph node (LN) cells from B6 donor mice were injected into sub-lethally irradiated major histocompatibility-mismatched CByB6F1 mice to induce BMF. Anti-Ly6G antibody injection worsened cytopenias and BM hypoplasia, and they increased BM CD4 and CD8 T cell infiltration. In contrast, anti-Ly6G antibody injection in the minor histocompatibility-mismatched C.B10 BMF model improved platelet counts and reduced BM CD8 T cells. The pathogenic and protective effects in the two models correlated with differential anti-Ly6G antibody modulation of G-MDSCs: in the CByB6F1 model, anti-Ly6G antibody eradicated G-MDSCs in blood and BM while in the C.B10 model the same antibody generated a novel G-MDSC cell population, of identical Ly6C lowCD11b + phenotype but intermediate Ly6G expression, which was not present in the CByB6F1 animals after antibody injection. When we examined the efficacy of G-MDSCs in C.B10 BMF: Ly6G + cells were enriched from BM of normal C.B10 donors (94%-97% Ly6C lowLy6G +CD11b +), and injected at the time of marrow failure initiation. Mice infused with Ly6G + cells had significantly higher levels of WBC, RBC, platelets, and total BM cells, decreased BM CD4 and CD8 T cell infiltration, and improved BM cellularity. These results indicated a protective role of G-MDSCs. When G-MDSCs were injected at day 3 after LN cell infusion, treated mice again had higher levels of WBC, RBC, platelets, and total BM cells at day 14, alleviating BMF. As both prophylaxis and therapy, G-MDSCs decreased Fas expression and Annexin V binding of residual BM cells, suppressed intracellular levels of gamma interferon and tumor necrosis factor alpha, as well as cell proliferation protein Ki67 levels in BM CD4 and CD8 T cells, relative to BMF control mice. TotalSeq simultaneously detecting surface proteins and mRNA expression in whole BM mononuclear cells in the therapy model showed an increased proportion of myeloid cells and reduced proportion of T cells in marrow from G-MDSC-treated mice based on cell surface markers and marker gene expression (Fig. 1B). Gene pathway analysis revealed down-regulation of Fas expression and reduced program cell death in total BM cells and decreased expression of genes related to cell cycle in infiltrating T cells from Ly6G + cell-treated mice-both results consistent with suppression by G-MDSCs of T cell proliferation and protection of target BM cells from apoptosis. In vitro culture of T cells from B6 mice with G-MDSCs which had been isolated from C.B10 BM cells showed dose-dependent suppression of T cell proliferation.In conclusion, our results demonstrate an active role of G-MDSCs in protecting BM from immune-mediated destruction, by suppression of T cell proliferation in the BM. G-MDSCs might have clinical application as treatment in human aplastic anemia and other immune-mediated and autoimmune diseases. [Display omitted] DisclosuresYoung: Novartis: Research Funding.

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy.

The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.

Targeting of myeloid-derived suppressor cells by all-trans retinoic acid as host-directed therapy for human tuberculosis

Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.

TRAF6 Regulates the Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Tumor-Bearing Host.

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous cells derived from the bone marrow and they are the major component of the tumor-induced immunosuppressive environment. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, catalyzes the polyubiquitination of target proteins. TRAF6 plays a critical role in modulating the immune system. However, whether TRAF6 is involved in the regulation of MDSCs has not been thoroughly elucidated to date. In this study, we found that the expression of TRAF6 in MDSCs derived from tumor tissue was significantly upregulated compared with that of MDSCs from spleen of tumor-bearing mice. Knockdown of TRAF6 remarkably attenuated the immunosuppressive effects of MDSCs. Mechanistically, TRAF6 might improve the immunosuppression of MDSCs by mediating K63-linked polyubiquitination and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Additionally, it was discovered that the accumulation of MDSCs was abnormal in peripheral blood of lung cancer patients. TRAF6 and arginase 1 were highly expressed in MDSCs of patients with lung cancer. Taken together, our study demonstrated that TRAF6 participates in promoting the immunosuppressive function of MDSCs and provided a potential target for antitumor immunotherapy.

The Immunoregulatory Role of Myeloid-Derived Suppressor Cells in the Pathogenesis of Rheumatoid Arthritis.

Myeloid-derived suppressor cells (MDSCs) are a group of cells that regulate the immune response and exert immunosuppressive effects on various immune cells. Current studies indicate that MDSCs have both anti-inflammatory effects and proinflammatory effects on rheumatoid arthritis (RA) and RA animal models. MDSCs inhibit CD4+ T cells, which secrete proinflammatory factors such as IFN-γ, IL-2, IL-6, IL-17, and TNF-α, by inhibiting iNOS, ROS, and IFN-γ and promoting the production of the anti-inflammatory factor IL-10. MDSCs can suppress dendritic cells by reducing MHC-II and CD86 expression, expand Treg cells in vitro through the action of IL-10, inhibit B cells through NO and PGE2, and promote Th17 cell responses by secreting IL-1β. As a type of osteoclast precursor cell, MDSCs can differentiate into osteoclasts through activation of the NF-κB pathway via IL-1α. Overall, our study reviews the research progress related to MDSCs in RA, focusing on the effects of MDSCs on various types of cells and aiming to provide ideas to help reveal the important role of MDSCs in RA.

Therapeutic anti-psoriatic effects of myeloid-derived suppressor cells in combination with systemic tacrolimus (FK-506) in an imiquimod-induced mouse model of psoriasis

Although tacrolimus (FK-506) has been shown to be an effective monotherapy for psoriasis, it does not always work well. Currently, combination therapy is frequently used to manage psoriasis because clinical trials have shown it may provide additive or synergistic benefits and reduce risks of adverse effects. Myeloid-derived suppressor cells (MDSCs) have potent immunomodulatory and anti-inflammatory properties in autoimmune diseases. We previously reported that MDSCs had protective effects in a murine model of imiquimod (IMQ)-induced psoriasis. The present study was undertaken to investigate the systemic immunomodulatory and therapeutic efficacy effects of MDSC plus FK-506 in an IMQ-induced mouse model of psoriasis and to investigate the immunomodulatory mechanisms involved. Systemic MDSC plus FK-506 therapy was found to have a significant anti-psoriatic effect in the murine model, to reduce levels of pro-inflammatory cytokines Th1 cytokines (TNF-α and IFN-γ) and Th17 cytokines (IL-17A and IL-23) in serum and skin. However, treatment with MDSCs or FK-506 alone had little impact. Furthermore, the anti-psoriatic effects of MDSC plus FK-506 were associated with histopathological reductions in inflammatory infiltration, epidermal hyperplasia, and hyperkeratosis. In addition, this combined treatment also attenuated IMQ-induced splenomegaly, and increased the proportion of CD4+CD25+FoxP3+ regulatory T (Treg) cells and decreased the proportions of CD4+IFN-γ+ Th1 cells and CD4+IL-17+ Th17 cells in spleen. Taken together, our results show systemic combination therapy with MDSCs and FK-506 had a better therapeutic effect in our IMQ-induced psoriasis model than either agent alone, and suggest that this combinatorial therapy might be useful for the management of autoimmune skin diseases like psoriasis.

The role and mechanism of myeloid-derived suppressor cells in mice with nonalcoholic steatohepatitis

Objective To investigate the effects of myeloid-derived suppressor cells (MDSCs) on nonalcoholic steatohepatitis mice. Methods ⑴ Male C57BL/6 mice aged 6-8 weeks were randomly divided into normal diet group, CDAA group(choline deficient amino acid diet) and CSAA group (choline sufficient amino acid diet). ⑵ After the success of the non-alcoholic steatohepatitis model, serum was collected from some mice to detect biochemical indexes; Liver tissue was retained for microscopic observation by hematoxylin-eosin (HE) staining; The changes of T cell subsets in peripheral blood of mice in each group were detected by flow cytometry. In addition, The proportion and subtype of CD11b+ Gr-1+ MDSCs cells in liver, spleen, blood and bone marrow were also detected by flow cytometry. ⑶ The bone marrow-derived Gr-1highLy-6G+ was purified by magnetic bead sorting technique, and the purified Gr-1highLy-6G+ was transferred into non-alcoholic steatohepatitis (NASH) mice by tail vein injection. The role of MDSCs in NASH was analyzed by detection of serological indexes of liver function and pathological dyeing. Results ⑴ There was no significant difference in body weight and liver index between the groups (P>0.05). Serological indicators: alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood glucose, interleukin (IL)-6 and interferon-γ (INF-γ) in the model group were significantly higher than those in the normal group (P 0.05); the MDSCs of liver in CDAA group is lower than that of normal group (P normal group (P<0.01), CD11b+ Gr-1dimLy-6G-(M-MDSC) showed a downward trend, CDAA group < normal group; ⑶ Serum AST and ALT levels of NASH mice who receiving Gr-1highLy-6G+ MDSCs from normal bone marrow were significantly decreased (P<0.001), and histopathological changes were alleviated. Conclusions ⑴ The NASA mouse model can be successfully established on the CDAA diet. ⑵ The CDAA-induced NASH mice may have immune dysfunction, mainly manifesting in the change of bone marrow MDSCs subpopulations and the increase of CD11b+ Gr-1highLy-6G+ (G-MDSC). ⑶ MDSCs derived from normal mouse bone marrow can alleviate the pathological changes of NASH. Key words: Myeloid-derived suppressor cells; Non-alcoholic steatohepatitis; T-lymphocytes; Interleukin-6; Mice

Myeloid derived suppressor cells contribute to the malignant progression of oral squamous cell carcinoma.

PurposeThe tumor-related myeloid derived suppressor cells (MDSCs), important immunosuppressive cells in tumor microenvironment, play an important role in the cancer progression. This study is aimed to investigate the crosstalk between MDSCs and oral squamous cell carcinoma (OSCC) cells and their role in the malignant progression of OSCC.MethodsImmunochemistry (IHC) was used to investigate the expression of CD33 in 200 OSCC, 36 premalignant. CD33+ MDSCs were sorted and enriched via magnetic-activated cell sorting (MACS) from OSCC patients or health donor, and their phenotypes were identified by flow cytometry. With a co-culture system of MDSCs and OSCC, the effects of MDSCs on OSCC proliferation, apoptosis, migration invasion, epithelial-mesenchymal transition (EMT), and vasculogenic mimicry formation (VM) formation were assessed, respectively. Besides, peripheral blood mononuclear cells (PBMCs) from health donor were cultured with OSCC supernatant, the level of MDSCs and expressions of Arginase (Arg-1) and inducible nitric oxide synthase (iNOS) were measured.ResultsThe number of MDSCs was increased in tumor tissues of OSCC patients, and was positively related to the T stage, pathological grade, lymph node metastasis and poor prognosis. Tumor-related MDSCs of the co-culture system promoted OSCC progression by contributing to cell proliferation, migration and invasion as well as inducing EMT and VM. In turn, OSCC cells had potential to induce MDSCs differentiation from PBMCs and increase the expression of Arg-1 and iNOS.ConclusionThese indicated that the crosstalk between MDSCs and tumor cells facilitated the malignant progression of OSCC cells and the immune suppressive properties of MDSCs, which may provide new insights into tumor treatment on targeting tumor-associated immunosuppressive cells.

G-MDSC-derived exosomes attenuate collagen-induced arthritis by impairing Th1 and Th17 cell responses

The therapeutic effect of myeloid-derived suppressor cells (MDSCs) in mice with collagen-induced arthritis (CIA) remains controversial. We analyzed the role of exosomes derived from granulocytic MDSCs (G-MDSCs) in CIA and explored the potential mechanism underlying the immunosuppressive effect. In CIA mice, G-MDSC-derived exosomes (G-exo) efficiently reduced the mean arthritis index, leukocyte infiltration and joint destruction. G-exo decreased the percentages of Th1 and Th17 cells both in vivo and in vitro. The miR-29a-3p and miR-93-5p contained in G-exo were verified to inhibit Th1 and Th17 cell differentiation by targeting T-bet and STAT3, respectively. Notably, the delivery of exogenous miR-29a-3p and miR-93-5p enhanced the ability of bone marrow-derived G-exo to attenuate arthritis progression in CIA mice. Exosomes derived from human MDSCs, which overexpressed miR-29a-3p and miR-93-5p, suppressed Th1 and Th17 cell differentiation in vitro. These data showed that G-exo alleviated CIA by suppressing Th1 and Th17 cell responses. Mechanistically, miR-29a-3p and miR-93-5p were verified to inhibit the differentiation of Th1 and Th17 cells, respectively. Our findings demonstrated the therapeutic potential of G-MDSC-derived exosomal miRNAs in autoimmune arthritis.

Myeloid Derived Suppressor Cells: Key Drivers of Immunosuppression in Ovarian Cancer.

The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BL/6, B6.129S7-Rag1tm1Mom/J, and B6.129P2(SJL)-Myd88tm1.1Defr/J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TMβ1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro. We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1tm1Mom/J mice compared to immunocompetent C57BL/6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BL/6 mice (p = 0.004) and in B6.129S7-Rag1tm1Mom/J mice (p = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines (p ≤ 0.02) and monocytic MDSC (p ≤ 0.01). Selective depletion of MDSC by anti-GR1 improved survival, certainly in comparison to mice treated with anti-CSF1 (p = 0.01—median survival 91 vs. 67.5 days). B6.129P2(SJL)-Myd88tm1.1Defr/J mice displayed to a longer median survival compared to C57BL/6 mice (90 vs. 76 days). MDSC activated by ID8-fLuc conditioned medium or ascites of tumor-bearing mice showed T cell suppressive functions in vitro. Based on these findings, we conclude that the adaptive immune system does not efficiently control tumor growth in the ID8-fLuc model. In addition, we discovered a prominent role for MDSC as the driver of immunosuppression in the ID8-fLuc ovarian cancer mouse model.

An Agent-based Model for Investigating the Effect of Myeloid-Derived Suppressor Cells and its Depletion on Tumor Immune Surveillance.

Background:To predict the behavior of biological systems, mathematical models of biological systems have been shown to be useful. In particular, mathematical models of tumor-immune system interactions have demonstrated promising results in prediction of different behaviors of tumor against the immune system.Methods:This study aimed at the introduction of a new model of tumor-immune system interaction, which includes tumor and immune cells as well as myeloid-derived suppressor cells (MDSCs). MDSCs are immune suppressor cells that help the tumor cells to escape the immune system. The structure of this model is agent-based which makes possible to investigate each component as a separate agent. Moreover, in this model, the effect of low dose 5-fluorouracil (5-FU) on MDSCs depletion was considered.Results:Based on the findings of this study, MDSCs had suppressive effect on increment of immune cell number which consequently result in tumor cells escape the immune cells. It has also been demonstrated that low-dose 5-FU could help immune system eliminate the tumor cells through MDSCs depletion.Conclusion:Using this new agent-based model, multiple injection of low-dose 5-FU could eliminate MDSCs and therefore might have the potential to be considered in treatment of cancers.

Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes

γδ T cells are a unique lymphocyte population that have been reported to have either anti- or pro-tumoral functions in several cancer types, but the mechanisms are underinvestigated. Exosomes, initially considered to be cellular "garbage dumpsters," are now implicated in mediating interactions with the cellular environment. Hypoxia is a common feature of solid tumors and is believed to alter tumor-derived exosomes (TEXs), which mediate the hypoxic evolution of the tumor microenvironment in return. This study sought to investigate whether TEXs mediate the anti- and pro-tumoral equilibrium of γδ T cells under different oxygen pressures in the tumor microenvironment. We show that TEXs can alter the expansion and cytotoxicity of γδ T cells in an HSP70-dependent but dendritic cell-independent manner. The stimulating effects of normoxic TEXs on γδ T-cell activity were absent from hypoxic TEXs, which enhanced the suppressive effect of myeloid-derived suppressor cells (MDSCs) on γδ T cells through a miR-21/PTEN/PD-L1 regulation axis. Finally, the therapeutic outcome benefited from combined miR-21 and PD-L1 targeting in oral squamous cell carcinoma (OSCC)-bearing immunocompetent mice. We conclude that oxygen pressure in the tumor microenvironment orchestrates an anti- and pro-tumoral γδ T-cell equilibrium by altering TEX content, which subsequently regulates MDSC function in a miR-21/PTEN/PD-L1-axis-dependent manner. Our results should prompt further investigation into integrated exosomal miRNA inhibition and immune checkpoint inhibitor therapeutic modalities for patients with OSCC.