scholarly journals Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor Inflammation

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Michael C. Schmid ◽  
Judith A. Varner
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Angiogenesis ◽  
Malignant Tumors ◽  
Critical Role ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Promote Tumor Growth ◽  
Bone Marrow Derived Cells

Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. Furthermore, we describe a subset of myeloid cells with immunosuppressive activity (known as myeloid-derived suppressor cells). Finally, we will comment on the mechanisms regulating myeloid cell recruitment to the tumor microenvironment and on the potential of myeloid cells as new targets for cancer therapy.

scholarly journals Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy

2014 ◽  
Vol 8 (1) ◽  
pp. 66-78 ◽  
Author(s):  
Vikram Mehraj ◽  
Mohammad-Ali Jenabian ◽  
Kishanda Vyboh ◽  
Jean-Pierre Routy
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Cell Function ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Immune Dysfunction ◽  
Hiv Pathogenesis ◽  
Host Restriction

Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication.

scholarly journals Mechanisms and Functional Significance of Human Tumor-infiltrating Myeloid Cells

2019 ◽  
Vol 4 (2) ◽  
pp. 41-49
Author(s):  
Amin Ramezani ◽  
Fatemeh Sadat Toghraie
Keyword(s):  
Stromal Cells ◽  
Cancer Biology ◽  
Critical Role ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Patient Prognosis ◽  
Tumor Associated Neutrophils

Myeloid cells as the major components of tumor-infiltrating leukocytes play critical roles in anti-tumor immunity. However, emerging evidences have revealed that soluble factors produced by tumor/stromal cells skew myeloid cells toward a tumor-promoting phenotype. Tumor-infiltrating myeloid cells (TIMs) including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs) are considered as the key mediators of tumor microenvironment (TME). TIMs have been shown to play important roles in various aspects of cancer biology and their presence is often linked to altered patient prognosis and survival. Regarding their critical role in TME, TIMs have been proposed as relevant targets of therapeutic strategies aimed at expanding immunostimulatory myeloid cell populations and depleting or modulating immunosuppressive ones. In this review, we briefly describe TIMs subsets and discuss the mechanisms by which TIMs induce immunosuppression, angiogenesis, and metastasis.

scholarly journals Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

2018 ◽  
Vol 19 (8) ◽  
pp. 2277
Author(s):  
Andrew Bryant ◽  
Borna Mehrad ◽  
Todd Brusko ◽  
James West ◽  
Lyle Moldawer
Keyword(s):  
Pulmonary Hypertension ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Pulmonary Vascular Remodeling ◽  
Adaptive Immune ◽  
Cell Changes ◽  
Transcription Factor Signaling

Myeloid–derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow–derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.

scholarly journals Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy

Blood ◽  
2010 ◽  
Vol 115 (7) ◽  
pp. 1461-1471 ◽  
Author(s):  
Saul J. Priceman ◽  
James L. Sung ◽  
Zory Shaposhnik ◽  
Jeremy B. Burton ◽  
Antoni X. Torres-Collado ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Antiangiogenic Therapy ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Compensatory Mechanism ◽  
Tumor Resistance ◽  
And Function ◽  
The Impact

Abstract Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b+F4/80+ tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b+Gr-1loLy6Chi mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti–VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

scholarly journals Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 654
Author(s):  
Vishnupriyan Kumar ◽  
Michael A. Giacomantonio ◽  
Shashi Gujar
Keyword(s):  
T Cell ◽  
Cancer Therapy ◽  
Critical Role ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Antitumor Effects ◽  
Cell Responses ◽  
Combination Strategies ◽  
Cell Immunity

Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.

scholarly journals The Metabolic Control of Myeloid Cells in the Tumor Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2960
Author(s):  
Eloise Ramel ◽  
Sebastian Lillo ◽  
Boutaina Daher ◽  
Marina Fioleau ◽  
Thomas Daubon ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Phenotypic Diversity ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Mass Cytometry ◽  
Cell Functions ◽  
Metabolic Checkpoints ◽  
The Impact

Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell’s metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.

scholarly journals Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model

2020 ◽  
Vol 69 (10) ◽  
pp. 2101-2112
Author(s):  
Philipp Metzger ◽  
Sabrina V. Kirchleitner ◽  
Daniel F. R. Boehmer ◽  
Christine Hörth ◽  
Angelika Eisele ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Critical Role ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Ductal Adenocarcinoma ◽  
Gm Csf ◽  
Immunosuppressive Tumor Microenvironment ◽  
And Function

Abstract Pancreatic ductal adenocarcinoma is characterized by a strong immunosuppressive network with a dense infiltration of myeloid cells including myeloid-derived suppressor cells (MDSC). Two distinct populations of MDSC have been defined: polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC). Several factors influence the development and function of MDSC including the transcription factor interferon regulatory factor 4 (IRF4). Here, we show that IRF4 deficiency accelerates tumor growth and reduces survival, accompanied with a dense tumor infiltration with PMN-MDSC and reduced numbers of CD8+ T cells. As IRF4 has been described to modulate myeloid cell development and function, particularly of PMN-MDSC, we analyzed its role using MDSC-specific IRF4 knockout mice with the Ly6G or LysM knock-in allele expressing Cre recombinase and Irf4flox. In GM-CSF-driven bone marrow cultures, IRF4 deficiency increased the frequency of MDSC-like cells with a strong T cell suppressive capacity. Myeloid (LysM)-specific depletion of IRF4 led to increased tumor weight and a moderate splenic M-MDSC expansion in tumor-bearing mice. PMN cell (Ly6G)-specific depletion of IRF4, however, did not influence tumor progression or MDSC accumulation in vivo in accordance with our finding that IRF4 is not expressed in PMN-MDSC. This study demonstrates a critical role of IRF4 in the generation of an immunosuppressive tumor microenvironment in pancreatic cancer, which is independent of IRF4 expression in PMN-MDSC.

scholarly journals Decoding the Role of Interleukin-30 in the Crosstalk between Cancer and Myeloid Cells

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 615
Author(s):  
Emma Di Carlo
Keyword(s):  
Tumor Microenvironment ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Experimental Models ◽  
Clinical Samples ◽  
Cellular Source ◽  
Immunotherapeutic Strategy ◽  
Cell Niche ◽  
The Relationship

In the last few years, a new actor hit the scene of the tumor microenvironment, the p28 subunit of interleukin (IL)-27, known as IL-30. Its molecular structure allows it to function as an autonomous cytokine and, alternatively, to pair with other subunits to form heterodimeric complexes and enables it to play different, and not fully elucidated, roles in immunity. However, data from the experimental models and clinical samples, suggest IL-30′s engagement in the relationship between cancer and myeloid cells, which fosters the tumor microenvironment and the cancer stem cell niche, boosting the disease progression. Activated myeloid cells are the primary cellular source and one of the targets of IL-30, which can also be produced by cancer cells, especially, in aggressive tumors, as observed in the breast and prostate. This review briefly reports on the immunobiology of IL-30 and related cytokines, by comparing mouse and human counterparts, and then focuses on the mechanisms whereby IL-30 amplifies intratumoral myeloid cell infiltrate and triggers a vicious cycle that worsens immunosuppression in the tumor microenvironment (TME) and constitutes a real threat for a successful immunotherapeutic strategy.

501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A536-A536
Author(s):  
Juan Dong ◽  
Cassandra Gilmore ◽  
Hieu Ta ◽  
Keman Zhang ◽  
Sarah Stone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Checkpoint Protein ◽  
Suppressive Function

BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

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