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Activated neutrophils exert myeloid-derived suppressor cell activity damaging T cells beyond repair.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) have the capacity to suppress T-cell-mediated immune responses and impact the clinical outcome of cancer, infections, and transplantation settings. Although MDSCs were initially described as bone marrow-derived immature myeloid cells (either monocytic or granulocytic MDSCs), mature neutrophils have been shown to exert MDSC activity toward T cells in ways that remain unclear. In this study, we demonstrated that human neutrophils from both healthy donors and cancer patients do not exert MDSC activity unless they are activated. By using neutrophils with genetically well-defined defects, we found that reactive oxygen species (ROS) and granule-derived constituents are required for MDSC activity after direct CD11b-dependent interactions between neutrophils and T cells. In addition to these cellular interactions, neutrophils are engaged in the uptake of pieces of T-cell membrane, a process called trogocytosis. Together, these interactions led to changes in T-cell morphology, mitochondrial dysfunction, and adenosine triphosphate depletion, as indicated by electron microscopy, mass spectrometry, and metabolic parameters. Our studies characterize the different steps by which activated mature neutrophils induce functional T-cell nonresponsiveness and irreparable cell damage.

SUBMITTER: Aarts CEM

PROVIDER: S-EPMC6880908 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Activated neutrophils exert myeloid-derived suppressor cell activity, damaging T cells beyond repair

Project description:Myeloid-derived suppressor cells (MDSCs) have the capacity to suppress T cell-mediated immune responses, and impact clinical outcome of cancer, infections and transplantation settings. Although MDSCs were initially described as bone-marrow-derived immature myeloid cells (either monocytic [m-MDSC] or granulocytic [g-MDSC]), also mature neutrophils have been shown to exert MDSC activity towards T cells, in ways that so far remained unclear. In this study, we demonstrate that human neutrophils – both from healthy donors and cancer patients – do not exert MDSC activity unless they are activated. Using neutrophils with genetically well-defined defects, we found that reactive oxygen species (ROS) and granule-derived constituents are required for MDSC activity after direct CD11b-dependent neutrophil-T cell interactions. Besides these cellular interactions, neutrophils were engaged in the uptake of pieces of T cell membrane, a process called trogocytosis. Together, these interactions led to changes in T cell morphology, mitochondrial dysfunction and ATP depletion, as indicated by electron microscopy, mass spectrometry and metabolic parameters. Our studies characterize the different steps by which activated mature neutrophils induce functional T cell non-responsiveness and irreparable cell damage.

2020-05-07 | PXD010508 | Pride

Bone Marrow Neutrophils of Multiple Myeloma Patients Exhibit Myeloid-Derived Suppressor Cell Activity.

Project description:Activated normal density granulocytes (NDGs) can suppress T-cell responses in a similar way as myeloid-derived suppressor cells (MDSCs). In this study, we tested the hypothesis that NDGs from blood and bone marrow of multiple myeloma (MM) patients have the ability to suppress T-cells, as MDSC. MM is an incurable plasma cell malignancy of the bone marrow. Like most malignancies, myeloma cells alter its microenvironment to promote tumor growth, including inhibition of the immune system. We found that MM NDG from the bone marrow suppressed proliferation of T-cells, in contrast to healthy donors. The inhibitory effect could not be explained by changed levels of mature or immature NDG in the bone marrow. Moreover, NDG isolated from the blood of both myeloma patients and healthy individuals could inhibit T-cell proliferation and IFN-γ production. On the contrary to previous studies, blood NDGs did not have to be preactivated to mediate suppressive effects. Instead, they became activated during coculture, indicating that contact with activated T-cells is important for their ability to regulate T-cells. The inhibitory effect was dependent on the production of reactive oxygen species and could be reverted by the addition of its inhibitor, catalase. Our findings suggest that blood NDGs from MM patients are suppressive, but no more than NDGs from healthy donors. However, only bone marrow NDG from MM patients exhibited MDSC function. This MDSC-like suppression mediated by bone marrow NDG could be important for the growth of malignant plasma cells in MM patients.

| S-EPMC8369183 | biostudies-literature

Myeloid-derived Suppressor Cells in Colorectal Cancer

Project description:The aim of the study is to evaluate whether the preoperative level of myeloid-derived suppressor cells is associated with postoperative complications classified by Clavien-Dindo categories. Levels of all MDSC, polymorphonuclear MDSC (PMNMDSC), monocytic MDSC (MMDSC), early-stage MDSC (EMDSC) and monocytic to polymorphonuclear MDSC ratio (M/PMN MDCS) were established and compared in patients with postoperative complications, severe postoperative complications (>= IIIA according to Clavien-Dindo) and severe septic complications.

| 2381881 | ecrin-mdr-crc

Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils.

Project description:The role of myeloid cells in supporting cancer growth is well established. Most work has focused on myeloid-derived suppressor cells (MDSC) that accumulate in tumor-bearing animals, but tumor-associated neutrophils (TAN) are also known to be capable of augmenting tumor growth. However, little is known about their evolution, phenotype, and relationship to naïve neutrophils (NN) and to the granulocytic fraction of MDSC (G-MDSC).In the current study, a transcriptomics approach was used in mice to compare these cell types. Our data show that the three populations of neutrophils are significantly different in their mRNA profiles with NN and G-MDSC being more closely related to each other than to TAN. Structural genes and genes related to cell-cytotoxicity (i.e. respiratory burst) were significantly down-regulated in TAN. In contrast, many immune-related genes and pathways, including genes related to the antigen presenting complex (e.g. all six MHC-II complex genes), and cytokines (e.g. TNF-?, IL-1-?/?), were up-regulated in G-MDSC, and further up-regulated in TAN. Thirteen of the 25 chemokines tested were markedly up-regulated in TAN compared to NN, including striking up-regulation of chemoattractants for T/B-cells, neutrophils and macrophages.This study characterizes different populations of neutrophils related to cancer, pointing out the major differences between TAN and the other neutrophil populations.

| S-EPMC3279406 | biostudies-literature

Human Isogenic Cell Line Models for Neutrophils and Myeloid-Derived Suppressor Cells.

Project description:Neutrophils with immunosuppressive activity are polymorphonuclear myeloid-derived suppressor cells (MDSCs) and may contribute to the resistance to cancer immunotherapy. A major gap for understanding and targeting these cells is the paucity of cell line models with cardinal features of human immunosuppressive neutrophils and their normal counterparts, especially in an isogenic manner. To address this issue, we employ the human promyelocytic cell line HL60 and use DMSO and cytokines (granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin 6 (IL6)) to induce the formation of either neutrophils or MDSCs. The induced MDSCs are CD11b+ CD33+ HLA-DR-/low and are heterogeneous for CD15 and CD14 expression. The induced MDSCs abrogate IL2 production and activation-induced cell death of the human T cell line Jurkat stimulated by CD3/CD28 antibodies, whereas the induced neutrophils enhance IL2 production from Jurkat cells. The induced MDSCs upregulate the expression of C/EBPβ, STAT3, VEGFR1, FATP2 and S100A8. Lastly, the immunosuppressive activity of the induced MDSCs is inhibited by all-trans retinoic acid and STAT3 inhibitor BP-1-102 through cellular differentiation and dedifferentiation mechanisms, respectively. Together, our study establishes a human isogenic cell line system for neutrophils and MDSCs and this system is expected to facilitate future studies on the biology and therapeutics of human immunosuppressive neutrophils.

| S-EPMC7590135 | biostudies-literature

Neutrophils and polymorphonuclear myeloid-derived suppressor cells: an emerging battleground in cancer therapy.

Project description:Neutrophils are central mediators of innate and adaptive immunity and first responders to tissue damage. Although vital to our health, their activation, function, and resolution are critical to preventing chronic inflammation that may contribute to carcinogenesis. Cancers are associated with the expansion of the neutrophil compartment with an escalation in the number of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the peripheral circulation and tumor microenvironment. Although phenotypically similar to classically activated neutrophils, PMN-MDSC is pathologically activated and immunosuppressive in nature. They dynamically interact with other cell populations and tissue components and convey resistance to anticancer therapies while accelerating disease progression and metastatic spread. Cancer-associated neutrophilia and tumor infiltration of neutrophils are significant markers of poor outcomes in many cancers. Recently, there has been significant progress in the identification of molecular markers of PMN-MDSC providing insights into the central role of PMN-MDSC in the local tumor microenvironment as well as the systemic immune response in cancer. Further advances in sequencing and proteomics techniques will improve our understanding of their diverse functionalities and the complex molecular mechanisms at play. Targeting PMN-MDSC is currently one of the major focus areas in cancer research and several signaling pathways representing possible treatment targets have been identified. Positive results from preclinical studies clearly justify the current investigation in drug development and thus novel therapeutic strategies are being evaluated in clinical trials. In this review, we discuss the involvement of PMN-MDSC in cancer initiation and progression and their potential as therapeutic targets and clinical biomarkers in different cancers.

| S-EPMC9065109 | biostudies-literature

Targeting myeloid-derived suppressor cells in tumor immunotherapy: Current, future and beyond.

Project description:Myeloid-derived suppressor cells (MDSCs) are one of the major negative regulators in tumor microenvironment (TME) due to their potent immunosuppressive capacity. MDSCs are the products of myeloid progenitor abnormal differentiation in bone marrow, which inhibits the immune response mediated by T cells, natural killer cells and dendritic cells; promotes the generation of regulatory T cells and tumor-associated macrophages; drives the immune escape; and finally leads to tumor progression and metastasis. In this review, we highlight key features of MDSCs biology in TME that are being explored as potential targets for tumor immunotherapy. We discuss the therapies and approaches that aim to reprogram TME from immunosuppressive to immunostimulatory circumstance, which prevents MDSC immunosuppression activity; promotes MDSC differentiation; and impacts MDSC recruitment and abundance in tumor site. We also summarize current advances in the identification of rational combinatorial strategies to improve clinical efficacy and outcomes of cancer patients, via deeply understanding and pursuing the mechanisms and characterization of MDSCs generation and suppression in TME.

| S-EPMC10063857 | biostudies-literature

Myeloid-derived suppressor cell and macrophage exert distinct angiogenic and immunosuppressive effects in breast cancer.

Project description:The immunosuppressive tumor microenvironment is a key obstacle to hinder a cancer immunotherapy. Myeloid-derived suppressor cells (MDSCs) have been considered as a major player in immunosuppression. In this study, we find that tumor-infiltrating MDSCs (tiMDSCs) are less immunosuppressive than tumor-associated macrophages (TAMs) in multiple murine orthotopic breast tumor models. Compared to TAMs, tiMDSCs produce higher levels of pro-inflammatory factors and lower levels of anti-inflammatory factors. Furthermore, tiMDSCs are preferentially located in hypoxic areas and are more pro-angiogenic than TAMs. Consistent with these functional disparities, a shift from tiMDSCs to TAMs is observed during the progression of breast cancer. Moreover, infiltration of tiMDSCs is also noted in distal colonization of breast cancer cells in the lung. Taken together, our findings indicate that tiMDSCs are more pro-angiogenic and promote tumor initiation, while TAMs are more immunosuppressive and facilitate tumor immune evasion. This study suggests that selectively targeting on TAMs could alleviate the immunosuppressive tumor microenvironment and potentiate cancer immunotherapy.

| S-EPMC5589571 | biostudies-literature

Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression.

Project description:The expansion of myeloid derived suppressor cells (MDSCs), a suppressive population able to hamper the immune response against cancer, correlates with tumor progression and overall survival in several cancer types. We have previously shown that MDSCs can be induced in vitro from precursors present in the bone marrow and observed that these cells are able to actively proliferate in the presence of activated T cells, whose activation level is critical to drive the suppressive activity of MDSCs. Here we investigated at molecular level the mechanisms involved in the interplay between MDSCs and activated T cells. We found that activated T cells secrete IL-10 following interaction with MDSCs which, in turn, activates STAT3 phosphorylation on MDSCs then leading to B7-H1 expression. We also demonstrated that B7-H1+ MDSCs are responsible for immune suppression through a mechanism involving ARG-1 and IDO expression. Finally, we show that the expression of ligands B7-H1 and MHC class II both on in vitro-induced MDSCs and on MDSCs in the tumor microenvironment of cancer patients is paralleled by an increased expression of their respective receptors PD-1 and LAG-3 on T cells, two inhibitory molecules associated with T cell dysfunction. These findings highlight key molecules and interactions responsible for the extensive cross-talk between MDSCs and activated T cells that are at the basis of immune suppression.

| S-EPMC4811451 | biostudies-literature

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance.

Project description:Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types-including neutrophils and myeloid-derived suppressor cells-that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.

| S-EPMC7139844 | biostudies-literature

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