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Nature Reviews. Clinical Oncology Feb 2024Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise... (Review)
Review
Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise of cancer treatments that modulate the immune system. However, the immune system is complex and dynamic, and can have both tumour-suppressive and tumour-promoting effects. Understanding the full range of immune modulation in cancer is crucial to identifying more effective treatment strategies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that develop in association with chronic inflammation, which is a hallmark of cancer. Indeed, MDSCs accumulate in the tumour microenvironment, where they strongly inhibit anticancer functions of T cells and natural killer cells and exert a variety of other tumour-promoting effects. Emerging evidence indicates that MDSCs also contribute to resistance to cancer treatments, particularly immunotherapies. Conversely, treatment approaches designed to eliminate cancer cells can have important additional effects on MDSC function, which can be either positive or negative. In this Review, we discuss the interplay between MDSCs and various other cell types found in tumours as well as the mechanisms by which MDSCs promote tumour progression. We also discuss the relevance and implications of MDSCs for cancer therapy.
Topics: Humans; Myeloid-Derived Suppressor Cells; Neoplasms; Myeloid Cells; Immunotherapy; T-Lymphocytes; Tumor Microenvironment
PubMed: 38191922
DOI: 10.1038/s41571-023-00846-y -
Journal of Hepatology May 2022Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro,...
BACKGROUND & AIMS
Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis.
METHODS
Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14 and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems.
RESULTS
We found that stromal-myeloid coculture reduces the frequency CD14 cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9 scar-associated macrophage-like cells and towards CD163 Kupffer cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9 macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in the healthy liver.
CONCLUSIONS
Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.
LAY SUMMARY
The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.
Topics: Cell Differentiation; Humans; Interleukin-6; Liver Cirrhosis; Liver Diseases; Macrophages; Monocytes; RNA; Stromal Cells
PubMed: 35074474
DOI: 10.1016/j.jhep.2021.12.036 -
The Journal of Clinical Investigation Nov 2023The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor...
The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer.
Topics: Humans; Animals; Mice; Myeloid-Derived Suppressor Cells; Triggering Receptor Expressed on Myeloid Cells-1; Myeloid Cells; Cell Line, Tumor; Melanoma; T-Lymphocytes, Cytotoxic; Disease Models, Animal; Tumor Microenvironment
PubMed: 37651197
DOI: 10.1172/JCI167951 -
Cell Metabolism Jan 2024Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and...
Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.
Topics: Mice; Animals; Humans; Glioblastoma; Creatine; Hypoxia; Myeloid Cells; Myeloid Progenitor Cells; Cell Line, Tumor
PubMed: 38134929
DOI: 10.1016/j.cmet.2023.11.013 -
Current Opinion in Immunology Dec 2021Myeloid cells (macrophages, monocytes, dendritic cells, and granulocytes) survey the body for signs of infection and damage and regulate tissue homeostasis,... (Review)
Review
Myeloid cells (macrophages, monocytes, dendritic cells, and granulocytes) survey the body for signs of infection and damage and regulate tissue homeostasis, organogenesis, and immunity. They express receptors that initiate the inflammatory response, send signals that alter the vascular and cytokine milieu, and oversee the recruitment, differentiation, and activation of other myeloid and adaptive immune cells. Their activation must therefore be tightly regulated, optimized for maximal innate-immune protection with a minimum of collateral tissue damage or disorganization. In this review we discuss what it means for myeloid cells to become activated, with emphasis on the receptors and signaling molecules important for the recognition of pathogen-associated and damage-associated molecular patterns. We also outline how these signals are regulated by the steric properties of proteins, by adhesive and cytoskeletal interactions, and by negative feedback to keep inflammation in check and support healthy tissue development and homeostasis. Throughout the text we highlight recent publications and reviews and direct readers therein for a comprehensive bibliography.
Topics: Animals; Cell Differentiation; Cytoskeleton; Homeostasis; Humans; Immunity, Innate; Inflammation; Myeloid Cells; Organogenesis; Signal Transduction
PubMed: 34601225
DOI: 10.1016/j.coi.2021.09.004 -
Proceedings of the National Academy of... Jan 2022Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory...
Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory responses are poorly understood. Here, we show that TANK-binding kinase 1 (TBK1) serves as a vital regulator of proinflammatory macrophage function and protects against tissue inflammation. Myeloid cell-conditional Tbk1 knockout (MKO) mice spontaneously developed adipose hypertrophy and metabolic disorders at old ages, associated with increased adipose tissue M1 macrophage infiltration and proinflammatory cytokine expression. When fed with a high-fat diet, the -MKO mice also displayed exacerbated hepatic inflammation and insulin resistance, developing symptoms of nonalcoholic steatohepatitis. Furthermore, myeloid cell-specific TBK1 ablation exacerbates inflammation in experimental colitis. Mechanistically, TBK1 functions in macrophages to suppress the NF-κB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1β. Ablation of IL-1 receptor 1 (IL-1R1) eliminates the inflammatory symptoms of -MKO mice. These results establish TBK1 as a pivotal anti-inflammatory mediator that restricts inflammation in different disease models.
Topics: Adipose Tissue; Animals; Biomarkers; Colitis; Cytokines; Diet, High-Fat; Disease Models, Animal; Disease Susceptibility; Gene Expression Regulation; Glucose; Hypertrophy; Immunomodulation; Inflammation; Inflammation Mediators; Insulin Resistance; Mice; Mice, Knockout; Myeloid Cells; Non-alcoholic Fatty Liver Disease; Organ Specificity; Protein Serine-Threonine Kinases; Receptors, Interleukin-1; Signal Transduction
PubMed: 35074921
DOI: 10.1073/pnas.2107742119 -
Arthritis & Rheumatology (Hoboken, N.J.) Feb 2022In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin.
Expansion of Fcγ Receptor IIIa-Positive Macrophages, Ficolin 1-Positive Monocyte-Derived Dendritic Cells, and Plasmacytoid Dendritic Cells Associated With Severe Skin Disease in Systemic Sclerosis.
OBJECTIVE
In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin.
METHODS
We analyzed the transcriptomes of 2,465 myeloid cells from skin biopsy specimens from 12 dcSSc patients and 10 healthy control subjects using single-cell RNA sequencing. Monocyte-derived dendritic cells (mo-DCs) were assessed using immunohistochemical staining and immunofluorescence analyses targeting ficolin-1 (FCN-1).
RESULTS
A t-distributed stochastic neighbor embedding analysis of single-cell transcriptome data revealed 12 myeloid cell clusters, 9 of which paralleled previously described healthy control macrophage/DC clusters, and 3 of which were dcSSc-specific myeloid cell clusters. One SSc-associated macrophage cluster, highly expressing Fcγ receptor IIIA, was suggested on pseudotime analysis to be derived from normal CCR1+ and MARCO+ macrophages. A second SSc-associated myeloid population highly expressed monocyte markers FCN-1, epiregulin, S100A8, and S100A9, but was closely related to type 2 conventional DCs on pseudotime analysis and identified as mo-DCs. Mo-DCs were associated with more severe skin disease. Proliferating macrophages and plasmacytoid DCs were detected almost exclusively in dcSSc skin, the latter clustering with B cells and apparently derived from lymphoid progenitors.
CONCLUSION
Transcriptional signatures in these and other myeloid populations indicate innate immune system activation, possibly through Toll-like receptors and highly up-regulated chemokines. However, the appearance and activation of myeloid cells varies between patients, indicating potential differences in the underlying pathogenesis and/or temporal disease activity in dcSSc.
Topics: Dendritic Cells; Humans; Lectins; Macrophages; Monocytes; Receptors, IgG; Scleroderma, Diffuse; Severity of Illness Index; Ficolins
PubMed: 34042322
DOI: 10.1002/art.41813 -
Cold Spring Harbor Perspectives in... May 2020Metastatic disease is the leading cause of death in patients with solid cancers. The progression to metastasis is a multistep process that involves detachment of tumor... (Review)
Review
Metastatic disease is the leading cause of death in patients with solid cancers. The progression to metastasis is a multistep process that involves detachment of tumor cells from their constraining basement membrane at the primary site, migration and intravasation into the circulation, survival in the circulation, extravasation into the secondary organ, and survival and growth at the secondary site. During these steps, tumor and immune cells interact and influence each other both within the tumor microenvironment and systemically. In particular, myeloid cells such as monocytes, macrophages, neutrophils, and myeloid-derived suppressor cells (myeloid regulatory cells) have been shown to play important roles in the metastatic process. These interactions open new avenues for targeting cancer metastasis, especially given the increasing interest in development of cancer immunotherapies. In this review, we describe the currently reported pathways and mechanisms involved in myeloid cell enhancement of the metastatic cascade.
Topics: Animals; Humans; Immunotherapy; Myeloid Cells; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Tumor Microenvironment
PubMed: 31548218
DOI: 10.1101/cshperspect.a038026 -
Cancer Cell Jun 2024Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic...
Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.
Topics: Membrane Glycoproteins; Receptors, Immunologic; Humans; Animals; Mice; Glioblastoma; Myeloid Cells; Central Nervous System Neoplasms; Cell Line, Tumor; Mice, Inbred C57BL; Brain Neoplasms
PubMed: 38788719
DOI: 10.1016/j.ccell.2024.05.001 -
Journal of Experimental & Clinical... Dec 2023Myeloid cells (granulocytes and monocytes/macrophages) play an important role in neuroblastoma. By inducing a complex immunosuppressive network, myeloid cells pose a... (Review)
Review
Myeloid cells (granulocytes and monocytes/macrophages) play an important role in neuroblastoma. By inducing a complex immunosuppressive network, myeloid cells pose a challenge for the adaptive immune system to eliminate tumor cells, especially in high-risk neuroblastoma. This review first summarizes the pro- and anti-tumorigenic functions of myeloid cells, including granulocytes, monocytes, macrophages, and myeloid-derived suppressor cells (MDSC) during the development and progression of neuroblastoma. Secondly, we discuss how myeloid cells are engaged in the current treatment regimen and explore novel strategies to target these cells in neuroblastoma. These strategies include: (1) engaging myeloid cells as effector cells, (2) ablating myeloid cells or blocking the recruitment of myeloid cells to the tumor microenvironment and (3) reprogramming myeloid cells. Here we describe that despite their immunosuppressive traits, tumor-associated myeloid cells can still be engaged as effector cells, which is clear in anti-GD2 immunotherapy. However, their full potential is not yet reached, and myeloid cell engagement can be enhanced, for example by targeting the CD47/SIRPα axis. Though depletion of myeloid cells or blocking myeloid cell infiltration has been proven effective, this strategy also depletes possible effector cells for immunotherapy from the tumor microenvironment. Therefore, reprogramming of suppressive myeloid cells might be the optimal strategy, which reverses immunosuppressive traits, preserves myeloid cells as effectors of immunotherapy, and subsequently reactivates tumor-infiltrating T cells.
Topics: Humans; Neuroblastoma; Neoplasms; Myeloid Cells; Immunotherapy; Myeloid-Derived Suppressor Cells; Macrophages; Tumor Microenvironment
PubMed: 38087370
DOI: 10.1186/s13046-023-02913-9