Characteristics Of Myeloid-derived Suppressor Cells Research Articles

CD14-CD10-CD45+HLA-DR-SSC+ neutrophils may be granulocytic myeloid-derived suppressor cell-like cells and relate to disease progression in non-Hodgkin's lymphoma patients.

We explored the frequency of CD14-CD10-CD45+HLA-DR-SSC++ neutrophils (CD10- neutrophils) in patients with non-Hodgkin's lymphoma (NHL), and their immunologic characteristics and clinical significance. Patients with NHL who were newly diagnosed (NDP; n = 33), in remission (RMP; n = 28) and relapsed (RLP; n = 29) were included, and 47 volunteers were recruited as healthy controls (HCs). The frequency of CD10- neutrophils in the peripheral blood from HC and patients with NHL was detected. CD10- and CD10+ neutrophils were sorted, and their cytology was analyzed. CD3+ T cells were also isolated and cultured with the autologous CD10- or CD10+ neutrophils, after which the proliferation and death rates of T cells were determined. The levels of arginase-1 (Arg-1) and reactive oxygen species (ROS) in CD10+ or CD10- neutrophils were examined. Few CD10- neutrophils were detected in HCs but were significantly elevated in patients with NHL, especially in NDP and RLP. In addition, CD10- neutrophils in NDP with advanced stage and high risk were markedly higher than those in NDP with limited stage and low risk. In RMP and RLP, the relapse-free survival and overall survival in patients with high CD10- neutrophils were shorter than those with low CD10- neutrophils. CD10- neutrophils from patients with NHL, which mainly consist of immature neutrophils, inhibit T-cell proliferation and facilitate T-cell death. Furthermore, a significant increase was observed in Arg-1 expression, along with an increase to a certain extent in ROS. CD10- neutrophils in patients with NHL have characteristics of myeloid-derived suppressor cells and may be related to disease progression and poor prognosis.

Alteration of functionality and differentiation directed by changing gene expression patterns in myeloid-derived suppressor cells (MDSCs) in tumor microenvironment and bone marrow through early to terminal phase of tumor progression.

Myeloid-derived suppressor cells are heterogenous immature myeloid lineage cells that can differentiate into neutrophils, monocytes, and dendritic cells as well. These cells have been characterized to have potent immunosuppressive capacity in neoplasia and a neoplastic chronic inflammatory microenvironment. Increased accumulation of myeloid-derived suppressor cells was reported with poor clinical outcomes in patients. They support neoplastic progression by abrogating antitumor immunity through inhibition of lymphocyte functions and directly by facilitating tumor development. Yet the shifting genetic signatures of this myeloid lineage cell toward immunosuppressive functionality in progressive tumor development remain elusive. We have attempted to identify the gene expression profile using lineage-specific markers of these unique myeloid lineage cells in a tumor microenvironment and bone marrow using a liquid transplantable mice tumor model to trace the changing influence of the tumor microenvironment on myeloid-derived suppressor cells. We analyzed the phenotype, functional shift, suppressive activity, differentiation status, and microarray-based gene expression profile of CD11b+Gr1+ lineage-specific cells isolated from the tumor microenvironment and bone marrow of 4 stages of tumor-bearing mice and compared them with control counterparts. Our analysis of differentially expressed genes of myeloid-derived suppressor cells isolated from bone marrow and the tumor microenvironment reveals unique gene expression patterns in the bone marrow and tumor microenvironment-derived myeloid-derived suppressor cells. It also suggests T-cell suppressive activity of myeloid-derived suppressor cells progressively increases toward the mid-to-late phase of the tumor and a significant differentiation bias of tumor site myeloid-derived suppressor cells toward macrophages, even in the presence of differentiating agents, indicating potential molecular characteristics of myeloid-derived suppressor cells in different stages of the tumor that can emerge as an intervention target.

Characterization of myeloid-derived suppressor cells (MDSCs) in endometrial cancer (2292)

Characterization of myeloid-derived suppressor cells (MDSCs) in endometrial cancer (2292)

Abstract 15542: Immuno-Footprint of Myeloid Clusters in Human Abdominal Aortic Aneurysm

Inflammation is a hallmark of abdominal aortic aneurysms (AAA) with central roles ascribed to myeloid lineage effector cells. However, the dynamics of circulating immune subsets, their interaction, and direct roles in AAA are not completely understood. Here, in human AAA and control blood, we used unbiased Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq) to investigate the complex spectrum of the proteome and transcriptome of the immune population, with refined characterization of immune subtypes in the peripheral blood. We also performed matched CITEseq for AAA tissues, allowing to define the fate and immuno-footprint of distinct immune clusters from blood to tissue. Fresh aortic specimens and blood from patients undergoing open AAA repair (n=5) and from healthy donors (n=2) were processed for CITEseq with a panel of antibodies encompassing 15 biologically relevant immune cell surface markers. After alignment, demultiplexing and cell cluster identification, analysis of proteo/transcriptome was performed in peripheral blood and in paired aneurysmal tissue datasets. Unsupervised clustering of CITEseq datasets from peripheral blood revealed eleven distinct clusters, with a unique signature of FCGR3A /CD16 + CD14 /CD14 lo monocytic populations in AAA patients, showing characteristics of myeloid-derived suppressor cells. Interestingly, we also unveiled that a subset of pro-inflammatory monocytes coerced solidly with activated platelets in monocyte-platelet complexes (MPC). MPC were selectively accrued in the blood of AAA. Pairwise analysis of blood and aortic tissue revealed increased accumulation of CD14 /CD14 + but not FCGR3A /CD16 + cells in AAA wall. In murine AAA modeled by angiotensin II infusion in ApoE -/- mice, we observed increased MPC in the circulation which correlated with increased inflammation in the aortic tissue. We further demonstrated that monocytes that bind to platelets are derived from the spleen. Splenectomy abrogated the formation of MPC and protected from AAA development in mice, similarly to targeted disruption of MPC. Here we show that interference with unbalanced circulating myeloid subsets and disruption of MPC are novel attractive avenues for therapeutic strategies in AAA.

Research advances of myeloid-derived suppressor cells in sepsis-induced immunosuppression

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Most patients with sepsis underwent a state of immune suppression after surviving the acute inflammatory response, and were susceptible to secondary nosocomial infections, leading to a prolonged hospitalization and increased mortality rate. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population with immunosuppressive activities, can contribute to the development of immunosuppression in patients with cancer and inhibit the host immune response, but the characteristics of MDSCs and their functional mechanism has not been fully addressed in the development of sepsis-induced immunosuppression. Thus, this review will summary the new findings on the mechanisms of MDSCs in septic immunosuppressionin order to provide ideas and directions for targeting MDSCs as treatment of septic immunosuppression.

Novel Characterization of Myeloid-Derived Suppressor Cells in Tumor Microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells generated in various pathologic conditions, which have been known to be key components of the tumor microenvironment (TME) involving in tumor immune tolerance. So MDSCs have been extensively researched recently. As its name suggests, immunosuppression is the widely accepted function of MDSCs. Aside from suppressing antitumor immune responses, MDSCs in the TME also stimulate tumor angiogenesis and metastasis, thereby promoting tumor growth and development. Therefore, altering the recruitment, expansion, activation, and immunosuppression of MDSCs could partially restore antitumor immunity. So, this view focused on the favorable TME conditions that promote the immunosuppressive effects of MDSCs and contribute to targeted therapies with increased precision for MDSCs.

Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection.

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous myeloid cells that expand in pathologic conditions as cancer, trauma, and infection. Although characterization of MDSCs is continuously revisited, the best feature is their suppressor activity. There are many markers for MDSC identification, it is distinctive that they express inducible nitric oxide synthase (iNOS) and arginase 1, which can mediate immune suppression. MDSCs can have a medullary origin as a result of emergency myelopoiesis, but also can have an extramedullary origin. Early studies on Trypanosoma cruzi infection showed severe immunosuppression, and several mechanisms involving parasite antigens and host cell mediators were described as inhibition of IL-2 and IL-2R. Another mechanism of immunosuppression involving tumor necrosis factor/interferon γ-dependent nitric oxide production by inducible nitric oxide synthase was also described. Moreover, other studies showed that nitric oxide was produced by CD11b+ Gr-1+ MDSCs in the spleen, and later iNOS and arginase 1 expressed in CD11b+Ly6C+Ly6Glo monocytic MDSC were found in spleen and heart of T. cruzi infected mice that suppressed T cell proliferation. Uncontrolled expansion of monocytic MDSCs leads to L-arginine depletion which hinders nitric oxide production leading to death. Supplement of L-arginine partially reverts L-arginine depletion and survival, suggesting that L-arginine could be administered along with anti-parasitical drugs. On the other hand, pharmacological inhibition of MDSCs leads to death in mice, suggesting that some expansion of MDSCs is needed for an efficient immune response. The role of signaling molecules mediating immune suppression as reactive oxygen species, reactive nitrogen species, as well as prostaglandin E2, characteristics of MDSCs, in T. cruzi infection is not fully understood. We review and discuss the role of these reactive species mediators produced by MDSCs. Finally, we discuss the latest results that link the SLAMF1 immune receptor with reactive oxygen species. Interaction of the parasite with the SLAMF1 modulates parasite virulence through myeloid cell infectivity and reactive oxygen species production. We discuss the possible strategies for targeting MDSCs and SLAMF1 receptor in acute Trypanosoma cruzi infection in mice, to evaluate a possible translational application in human acute infections.

New Insights into the Multifaceted Role of Myeloid-Derived Suppressor Cells (MDSCs) in High-Grade Gliomas: From Metabolic Reprograming, Immunosuppression, and Therapeutic Resistance to Current Strategies for Targeting MDSCs.

Cancer cells “hijack” host immune cells to promote growth, survival, and metastasis. The immune microenvironment of high-grade gliomas (HGG) is a complex and heterogeneous system, consisting of diverse cell types such as microglia, bone marrow-derived macrophages (BMDMs), myeloid-derived suppressor cells (MDSCs), dendritic cells, natural killer (NK) cells, and T-cells. Of these, MDSCs are one of the major tumor-infiltrating immune cells and are correlated not only with overall worse prognosis but also poor clinical outcomes. Upon entry from the bone marrow into the peripheral blood, spleen, as well as in tumor microenvironment (TME) in HGG patients, MDSCs deploy an array of mechanisms to perform their immune and non-immune suppressive functions. Here, we highlight the origin, function, and characterization of MDSCs and how they are recruited and metabolically reprogrammed in HGG. Furthermore, we discuss the mechanisms by which MDSCs contribute to immunosuppression and resistance to current therapies. Finally, we conclude by summarizing the emerging approaches for targeting MDSCs alone as a monotherapy or in combination with other standard-of-care therapies to improve the current treatment of high-grade glioma patients.

Myeloid-Derived Suppressor Cells: A New and Pivotal Player in Colorectal Cancer Progression.

Colorectal cancer (CRC) remains a devastating human malignancy with poor prognosis. Of the various factors, immune evasion mechanisms play pivotal roles in CRC progression and impede the effects of cancer therapy. Myeloid-derived suppressor cells (MDSCs) constitute an immature population of myeloid cells that are typical during tumor progression. These cells have the ability to induce strong immunosuppressive effects within the tumor microenvironment (TME) and promote CRC development. Indeed, MDSCs have been shown to accumulate in both tumor-bearing mice and CRC patients, and may therefore become an obstacle for cancer immunotherapy. Consequently, numerous studies have focused on the characterization of MDSCs and their immunosuppressive capacity, as well as developing novel approaches to suppress MDSCs function with different approaches. Current therapeutic strategies that target MDSCs in CRC include inhibition of their recruitment and alteration of their function, alone or in combination with other therapies including chemotherapy, radiotherapy and immunotherapy. Herein, we summarize the recent roles and mechanisms of MDSCs in CRC progression. In addition, a brief review of MDSC-targeting approaches for potential CRC therapy is presented.

Isolation and Functional Characterization of Myeloid-Derived Suppressor Cells in Infections Under High Containment.

The current absence of markers unique to MDSC, particularly those expanded during human infection, necessitate concurrent demonstration of their suppressive capacity to ensure unequivocal identification. This is further complicated by the array of heterogeneous markers used to characterize MDSC in various conditions and models. Standardization of phenotypic and functional characterization, as well as isolation, from infectious biological samples of patients, are critical for accurately reporting MDSC dynamics, function, organ abundance, and establishment of their therapeutic value in infectious diseases. To illustrate, we report on our established method for MDSC isolation from bronchoalveolar lavage fluid and peripheral blood of pulmonary TB patients, as well as functional impact on T cells by measuring T cell activation, proliferation, and cytokine production.

Recent advances in myeloid-derived suppressor cell biology.

In recent years, studying the role of myeloid-derived suppressor cells (MDSCs) in many pathological inflammatory conditions has become a very active research area. Although the role of MDSCs in cancer is relatively well established, their role in non-cancerous pathological conditions remains in its infancy resulting in much confusion. Our objectives in this review are to address some recent advances in MDSC research in order to minimize such confusion and to provide an insight into their function in the context of other diseases. The following topics will be specifically focused upon: (1) definition and characterization of MDSCs; (2) whether all MDSC populations consist of immature cells; (3) technical issues in MDSC isolation, estimation and characterization; (4) the origin of MDSCs and their anatomical distribution in health and disease; (5) mediators of MDSC expansion and accumulation; (6) factors that determine the expansion of one MDSC population over the other; (7) the Yin and Yang roles of MDSCs. Moreover, the functions of MDSCs will be addressed throughout the text.

The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid progenitor and precursor cells at different stages of differentiation, which play an important role in tumor immunosuppression. Glioma is the most common and deadliest primary malignant tumor of the brain, and ample evidence supports key contributions of MDSCs to the immunosuppressive tumor microenvironment, which is a key factor stimulating glioma progression. In this review, we summarize the source and characterization of MDSCs, discuss their immunosuppressive functions, and current approaches that target MDSCs for tumor control. Overall, the review provides insights into the roles of MDSC immunosuppression in the glioma microenvironment and suggests that MDSC control is a powerful cellular therapeutic target for currently incurable glioma tumors.

Decreased Circulating Myeloid Derived Suppressor Cells at First Follow-up Predict Favorable Response to Immunotherapy in a Randomized Trial of Nivolumab and Bevacizumab in Recurrent GBM

Abstract INTRODUCTION A potential barrier to successful immunotherapy response in glioblastoma (GBM) is myeloid-derived suppressor cells (MDSCs): an immature immunosuppressive cell elevated in the circulation and tumor of GBM patients. Given a limited set of biomarkers predictive of response to immunotherapy in GBM, we explored the change in MDSC levels with immunotherapy to predict treatment response. METHODS A retrospective analysis was performed on patients in a randomized, phase 2 study of nivolumab and bevacizumab at GBM first recurrence. Clinical and radiographic data were analyzed for disease progression or treatment response via Response Assessment in Neuro-Oncology (RANO) criteria. Blood was collected prior to treatment and at first imaging follow-up. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and analyzed. Characterization of circulating immune cells was performed using flow cytometry. RESULTS A total of 9 patients were identified as responders or nonresponders at a median time of 8.7 wk (range 6.9-10.0) after therapy initiation. MDSCs, as a percentage of total PBMCs, were elevated at baseline in responders compared to nonresponders (4.9% ± 0.7 vs 2.6% ± 0.2, P = .019), which reversed at follow up (1.8% ± 0.4 vs 5.8% ± 1.1, P = .032). There was a 6.4 fold decrease in MDSCs as a percentage of total PBMCs between baseline and first imaging follow-up in responders as compared to nonresponders (P = .001). When looking at subtypes of MDSCs, a 4.9 fold decrease in granulocytic MDSCs (G-MDSCs) was noted in responders over nonresponders (P = .010). Further investigation of this cohort by simultaneous single-cell analysis of transcriptome and surface epitopes is ongoing. CONCLUSION Differences in circulating MDSC levels that were specific to responders and nonresponders were seen both before and after therapy initialization, with decreases in MDSCs (specifically G-MDSCs) being correlated with treatment response. Characterization of MDSCs in the peripheral blood may be helpful in identifying GBM patients likely to benefit from immunotherapy.

Alteration of Myeloid-Derived Suppressor Cells, Chronic Inflammatory Cytokines, and Exosomal miRNA Contribute to the Peritoneal Immune Disorder of Patients With Endometriosis

Immunologic disorder has been reported to promote the progression of endometriosis (EMT). It has been known that myeloidderived suppressor cells (MDSCs) drive the progression of many types of diseases. Few studies have shown the relation between MDSCs and EMT. To test whether MDSCs play a role in the progression of EMT, we defined MDSCs, cytokines, and the exosomal microRNA (miRNA) profile in peritoneal fluid (PF) from EMT patients. Characteristics of MDSCs, regulatory T cells (Tregs) and effector T cells were quantified by flow cytometry. Peritoneal fluid monocyte chemoattractant protein (MCP) 1/3, hepatocyte growth factor (HGF), chemokine (C-X-C motif) ligand (CXCL) 1/2, and 13 other cytokines were performed by enzyme-linked immunosorbent assay kit. Exosomal miRNA sequencing was prepared from PF of 3 women with early-stage EMT, 3 women with advanced stage EMT, and 3 women from control group. Our results showed that accumulations of monocytic MDSCs (Mo-MDSCs) and Tregs were detected in advanced patients with EMT. Patients with EMT displayed a significantly higher production of PF CXCL1, CXCL2, MCP-1, MCP-3, and HGF as compared to those from controls. MicroRNA sequencing showed 13 exosomal miRNAs (miRNA-1908, -130b, -451a, -486-5p, -4488, -432, -342, -425, -505, -6508, -145, -365a, and -365b) which are involved in immune alteration and cell proliferation and were differentially expressed in patients with EMT (fold-change ± 2.0). In conclusion, our study revealed that Mo-MDSCs, inflammatory cytokines, and exosomal miRNA seem to be involved in the progression of EMT; however, the relation between Mo-MDSCs, cytokines, and miRNA needs further research.

Characterization of myeloid-derived suppressor cells and cytokines GM-CSF, IL-10 and MCP-1 in dogs with malignant melanoma receiving a GD3-based immunotherapy

Melanoma in humans and canines is an aggressive and highly metastatic cancer. The mucosal forms in both species share genetic and histopathologic features, making dogs a valuable spontaneous disease animal model. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells of myeloid origin with immunosuppressive capabilities, which are increased in many human cancers and contribute to tumor immune evasion. They are a possible target to improve immunotherapy outcomes. Current information regarding MDSCs in canines is minimal, limiting their use as translational model for the study of MDSCs. The objective of this study was to characterize major MDSCs subsets (monocytic and polymorphonuclear) and the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) in canines with malignant melanoma and to evaluate changes in MDSCs and the cytokines over time in response to a GD3-based active immunotherapy. Whole blood and serum collected from 30 healthy controls and 33 patients enrolled in the University of Florida melanoma vaccine trial were analyzed by flow cytometry with canine specific CD11b, MHCII and anti-human CD14 antibodies to assess ostensibly polymorphonuclear-MDSC (CD11b+ MHCII− CD14−) and monocytic-MDSC (CD11b+ MHCII− CD14+) subsets. IL-10, MCP-1 and both MDSCs subsets were significantly elevated in melanoma dogs versus controls. Both MDSCs subsets decreased significantly following GD3-based immunotherapy administration but no significant changes in cytokines were seen over time. To our knowledge, this is the first report documenting increased monocytic-MDSCs in canine melanoma. This is consistent with human malignant melanoma data, supporting dogs as a valuable model for therapeutic intervention studies.

Characterization of Myeloid-Derived Suppressor Cells and Tumor Associated Macrophages Using MultiOmyxTM Hyperplexed Immunofluorescence Assay in Hodgkin Lymphoma

Tumor microenvironment (TME) consists of heterogeneous subsets of myeloid cells and plays a crucial role in promoting cancer development and metastasis. Tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) all contribute to an immunologically permissive microenvironment for cancer cells. On basis of the expression of surface markers, MDSC can be further subdivided into granulocytic MDSC (G-MDSC, polymorphonuclear MDSC) and monocytic MDSC (M-MDSC). In solid tumors, these different myeloid cell populations are well characterized and extensively studied. However, in hematological malignancies the role of myeloid cell subsets has been less studied. A recent study showed increase in MDSC in the bone marrow (BM) at time of diagnosis in acute myeloid leukemia (AML) patients (Sun H. et al. Int J Hematol. 2015). Significantly higher numbers of G-MDSC and M-MDSC were present at diagnosis in classic Hodgkin lymphoma (cHL) (Romano A. et al. Br J Haematol. 2015). The accumulation of TAMs was also reported to be associated with poor prognosis in cHL (Steidl C. et al. N Engl J Med. 2010). Collectively, these results indicate that the tumor-resident myeloid cells play an important clinical role, thus highlighting the need for monitoring and deeper characterization of various myeloid subsets in hematological malignancies, especially in the tumor FFPE sections.Herein, we report an analysis of MDSCs and ‘protumoral’ M2 macrophages using MultiOmyx hyperplexed immunofluorescence (IF) assay in 9 clinical samples diagnosed with HL. MultiOmyx is a proprietary multi ‘omic’ technology that enables detection and visualization of up to 60 biomarkers on a single 4µM FFPE slide (Gerdes MJ. et al. PNAS 2013). The HL FFPE sections were stained with a 13-marker panel including Arginase 1, CD11b, CD14, CD15, CD16, CD33, CD68, CD163, HLA-DR, CD3, CD4, CD8 and FOXP3. We observed that both M-MDSC (Fig 1A, characterized as CD11b+CD14+CD15-CD33+HLA-DR-) and G-MDSC (Fig 1B, identified as CD11b+CD14-CD15+CD33+HLA-DR-) accumulated within the TME in all 9 HL samples, with higher frequency of G-MDSCs over M-MDSCs. Arg1 expression was detected exclusively in G-MDSC population (Fig 1C). The data also revealed an abundant M2 macrophages (Fig 1D, characterized as CD68+CD163+) present in all HL samples. The detection of both MDSCs and M2 macrophages in HL samples supports the hypothesis that these cells contribute to the establishment of an immunosuppressive TME. Using the MultiOmyx proprietary algorithm, which takes into account the staining patterns, we will next quantify the counts and density of different tumor-resident myeloid subsets and measure the spatial distance between each subset of tumor-resident myeloid cells to the neoplastic Reed-Sternberg cells. Correlation study will also be performed to determine if significant correlations exist between MDSCs and TAMs and how these immunosuppressive myeloid cells are related to the Regulatory T cells (CD3+CD4+FOXP3+) in HL samples. In addition to HL samples, the same 13-plexed panel will be utilized to characterize the myeloid cell population from AML patients.TAMs and MDSCs are emerging as potential biomarkers for diagnosis and prognosis of cancer as well as therapeutic targets. The comprehensive myeloid cells phenotyping offered by MultiOmyx 13-plexed panel has the potential to monitor the changes of immunosuppressive myeloid cells in response to immune modulating drugs such as MDSC-targeting drugs (e.g. PDE-5 inhibitors, COX-2 inhibitors), TAM-targeting agents (e.g. anti-CSF1R) and combined therapy in treatment of lymphoma and leukemia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 2067: Tumor-infiltrating PMN-MDSCs mediate sorafenib resistance in hepatocellular carcinoma through immune suppression

Abstract Background]: The mechanisms underlying the inherent or acquired resistance to sorafenib in advanced hepatocellular carcinoma (HCC) are not fully understood. We studied the role of myeloid-derived suppressor cells (MDSCs), a subset of bone marrow cells with immune-suppressive and proangiogenic activities, in sorafenib-treated mice and patients. Materials and Methods: An orthotopic mouse liver cancer model was established by implanting BNL cells to BALB/cByJNarl mice. Liver tumor-bearing mice were treated with sorafenib (5 mg/kg/d) for 1 week or 3 weeks from the day 8 after tumor cells implantation. For combination therapy, mice were treated sorafenib and anti-IL-6 Ab or its isotype control Ab (500 μg/every 3 days starting from day 4 for 4 doses). Tumor-infiltrating leukocytes (TILs) and leukocytes of other tissues including liver, spleen, peripheral blood, and bone marrow were isolated, and characterized by flow cytometry analysis. Morphological characteristics of MDSCs were determined by cytospin and Liu staining. Pro-inflammatory cytokines were detected by ELISA or mouse inflammatory cytokines beads array (BD). Paired HCC tissues from advanced HCC patients treated with sorafenib (before and post-sorafenib progression tissues) were evaluated for the expression of CD11b, CD15, and CD66b in TILs by immunohistochemistry. Results: In mice treated with sorafenib, the CD11b+Gr1+Ly6G+ MDSCs were significantly increased in liver tumors, but not in others tissues. Morphologically, these MDSCs were segmented nuclear PMN type cells. The analysis of TILs revealed that the percentage of total immune effectors (CD4+ or CD8+ IFN-γ-expressing T cells) versus total immune suppressors (IL-10 or TGF β-expressing CD4+ T cell, FOXP3-expressing CD4+ T cells) was lower in the tumors of sorafenib-treated mice than those of the vehicle-treated mice. The T cell proliferation capability was also significantly decreased in TILs of sorafenib-treated mice versus TILs of vehicle-treated mice. Multiple inflammatory cytokines including VEGF, G-CSF, MCP-1, and IL-6 were significantly increased in mouse liver tumors treated with sorafenib. When combined with sorafenib, anti-IL-6 antibody alleviated the early tumor-infiltration of Ly6G+ MDSCs, restored the proliferative activity of TILs, decreased the levels of pro-inflammatory factors in tumors, and suppressed the liver tumor growth synergistically. In 6 paired human HCC tissues, we found that 3 exhibited higher proportion of CD11b, CD15, or CD66b+ cells in post-sorafenib progression tissues than their pre-sorafenib treatment tissues. Conclusions: Our data indicate that tumor-infiltrating PMN type MDSCs and associated immunosuppression may be an important mechanism impeding the therapeutic efficacy of sorafenib in HCC. (This works was supported by MOST 105-2314-B-002-180). Citation Format: Chun-Jung Chang, Li-Chun Lu, Cher-wei Liang, Chih-Hung Hsu, Ann-Lii Cheng. Tumor-infiltrating PMN-MDSCs mediate sorafenib resistance in hepatocellular carcinoma through immune suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2017-2067

Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases

Myeloid-derived suppressor cells are immature myeloid cells with immunosuppressive properties. The review presents characteristics of myeloid-derived suppressor cells. It includes phenotype variants, mechanisms of the suppressive effect on the immune system, and tumor recruitment mechanisms of myeloid suppressors. It provides a brief description of works which studied myeloid suppressor in oncohematological diseases including multiple myeloma, lymphomas, and leukemias.

Frontline Science: Myeloid-derived suppressor cells (MDSCs) facilitate maternal-fetal tolerance in mice.

During successful pregnancy, a woman is immunologically tolerant of her genetically and antigenically disparate fetus, a state known as maternal-fetal tolerance. How this state is maintained has puzzled investigators for more than half a century. Diverse, immune and nonimmune mechanisms have been proposed; however, these mechanisms appear to be unrelated and to act independently. A population of immune suppressive cells called myeloid-derived suppressor cells (MDSCs) accumulates in pregnant mice and women. Given the profound immune suppressive function of MDSCs, it has been suggested that this cell population may facilitate successful pregnancy by contributing to maternal-fetal tolerance. We now report that myeloid cells with the characteristics of MDSCs not only accumulate in the circulation and uterus of female mice following mating but also suppress T cell activation and function in pregnant mice. Depletion of cells with the phenotype and function of MDSCs from gestation d 0.5 through d 7.5 resulted in implantation failure, increased T cell activation, and increased T cell infiltration into the uterus, whereas induction of MDSCs restored successful pregnancy and reduced T cell activation. MDSC-mediated suppression during pregnancy was accompanied by the down-regulation of L-selectin on naïve T cells and a reduced ability of naïve T cells to enter lymph nodes and become activated. Because MDSCs regulate many of the immune and nonimmune mechanisms previously attributed to maternal-fetal tolerance, MDSCs may be a unifying mechanism promoting maternal-fetal tolerance, and their induction may facilitate successful pregnancy in women who spontaneously abort or miscarry because of dysfunctional maternal-fetal tolerance.

Gr-1intCD11b+ myeloid-derived suppressor cells accumulate in corneal allograft and improve corneal allograft survival.

We identified the characteristics of myeloid-derived suppressor cells (MDSCs) and investigated their mechanism of induction and their functional role in allograft rejection using a murine corneal allograft model. In mice, MDSCs coexpress CD11b and myeloid differentiation antigen Gr-1. Gr-1+CD11b+ cells infiltrated allografted corneas between 4 d and 4 wk after surgery; however, the frequencies of Gr-1+CD11b+ cells were not different between accepted and rejected allografts or in peripheral blood or BM. Of interest, Gr-1intCD11b+ cells, but not Gr-1hiCD11b+ cells, infiltrated the accepted graft early after surgery and expressed high levels of immunosuppressive cytokines, including IL-10, TGF-β, and TNF-related apoptosis-inducing ligand. This population remained until 4 wk after surgery. In vitro, only high dose (>100 ng/ml) of IFN-γ plus GM-CSF could induce immunosuppressive cytokine expression in Gr-1intCD11b+ cells. Furthermore, adoptive transfer of Gr-1intCD11b+ cells reduced T cell infiltration, which improved graft survival. In conclusion, high-dose IFN-γ in allograft areas is essential for development of Gr-1intCD11b+ MDSCs in corneal allografts, and subtle environmental changes in the early period of the allograft can result in a large difference in graft survival.