-
Cellular & Molecular Immunology Jan 2020Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages,... (Review)
Review
Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages, are critical mediators for sterile and nonsterile inflammation, persistent inflammation, such as that which occurs in cancer, is known to disturb normal myelopoiesis. This disturbance leads to the generation of immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment, immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy. Indeed, various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies. These include anti-inflammatory agents, therapeutic blockade of the mobilization and survival of myeloid cells, and immunostimulatory adjuvants. More recently, immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells. In this review, we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.
Topics: Animals; Humans; Immune Checkpoint Inhibitors; Immune Tolerance; Macrophages; Myeloid-Derived Suppressor Cells; Myelopoiesis; Neoplasms; Tumor Microenvironment
PubMed: 31611651
DOI: 10.1038/s41423-019-0306-1 -
Leukemia & Lymphoma 2016Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of children with acute lymphoblastic leukemia. Positive outcomes are seen in... (Review)
Review
Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of children with acute lymphoblastic leukemia. Positive outcomes are seen in patients who are able to complete their entire prescribed course of asparaginase therapy. Toxicities associated with asparaginase use include hypersensitivity (clinical and subclinical), pancreatitis, thrombosis, encephalopathy, and liver dysfunction. Depending on the nature and severity of the toxicity, asparaginase therapy may be altered or discontinued in some patients. Clinical hypersensitivity is the most common asparaginase-associated toxicity requiring treatment discontinuation, occurring in up to 30% of patients receiving Escherichia coli-derived asparaginase. The ability to rapidly identify and manage asparaginase-associated toxicity will help ensure patients receive the maximal benefit from asparaginase therapy. This review will provide an overview of the common toxicities associated with asparaginase use and recommendations for treatment management.
Topics: Antineoplastic Agents; Asparaginase; Brain Diseases; Child; Child, Preschool; Connectin; Disease Management; Drug Hypersensitivity; Humans; Hyperglycemia; Hypertriglyceridemia; Liver; Microfilament Proteins; Myelopoiesis; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thrombosis
PubMed: 26457414
DOI: 10.3109/10428194.2015.1101098 -
Blood Jul 2020Our understanding of the genetics of acute myeloid leukemia (AML) development from myelodysplastic syndrome (MDS) has advanced significantly as a result of... (Review)
Review
Our understanding of the genetics of acute myeloid leukemia (AML) development from myelodysplastic syndrome (MDS) has advanced significantly as a result of next-generation sequencing technology. Although differences in cell biology and maturation exist between MDS and AML secondary to MDS, these 2 diseases are genetically related. MDS and secondary AML cells harbor mutations in many of the same genes and functional categories, including chromatin modification, DNA methylation, RNA splicing, cohesin complex, transcription factors, cell signaling, and DNA damage, confirming that they are a disease continuum. Differences in the frequency of mutated genes in MDS and secondary AML indicate that the order of mutation acquisition is not random during progression. In almost every case, disease progression is associated with clonal evolution, typically defined by the expansion or emergence of a subclone with a unique set of mutations. Monitoring tumor burden and clonal evolution using sequencing provides advantages over using the blast count, which underestimates tumor burden, and could allow for early detection of disease progression prior to clinical deterioration. In this review, we outline advances in the study of MDS to secondary AML progression, with a focus on the genetics of progression, and discuss the advantages of incorporating molecular genetic data in the diagnosis, classification, and monitoring of MDS to secondary AML progression. Because sequencing is becoming routine in the clinic, ongoing research is needed to define the optimal assay to use in different clinical situations and how the data can be used to improve outcomes for patients with MDS and secondary AML.
Topics: Cell Count; Clonal Evolution; DNA Methylation; DNA Mutational Analysis; Disease Progression; Epigenesis, Genetic; Hematopoietic Stem Cells; Humans; Lenalidomide; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Myelopoiesis; Neoplastic Stem Cells; Prognosis; Tumor Burden; Exome Sequencing; Whole Genome Sequencing
PubMed: 32430504
DOI: 10.1182/blood.2019000942 -
Cell Oct 2020A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic...
A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.
Topics: Animals; Bone Marrow Cells; Cell Proliferation; Disease Susceptibility; Hematopoietic Stem Cells; Homeostasis; Immunity; Interferon Type I; Iron; Kinetics; Lung; Macrophages; Mice, Inbred C57BL; Mycobacterium tuberculosis; Myeloid Cells; Myelopoiesis; Necrosis; Signal Transduction; Transcription, Genetic; Tuberculosis
PubMed: 33125891
DOI: 10.1016/j.cell.2020.09.062 -
Science Immunology Jan 2020PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell-specific PD-1...
PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell-specific PD-1 ablation on antitumor immunity has remained unclear because most studies have used either PD-1-blocking antibodies or complete PD-1 KO mice. We generated a conditional allele, which allowed myeloid-specific (PD-1) or T cell-specific (PD-1) targeting of gene. Compared with T cell-specific PD-1 ablation, myeloid cell-specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMPs), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSCs), express PD-1. In tumor-bearing PD-1 but not PD-1 mice, accumulation of GMP and MDSC was prevented, whereas systemic output of effector myeloid cells was increased. Myeloid cell-specific PD-1 ablation induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite preserved PD-1 expression in T cells. In PD-1-deficient myeloid progenitors, growth factors driving emergency myelopoiesis induced increased metabolic intermediates of glycolysis, pentose phosphate pathway, and TCA cycle but, most prominently, elevated cholesterol. Because cholesterol is required for differentiation of inflammatory macrophages and DC and promotes antigen-presenting function, our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade.
Topics: Animals; Cell Differentiation; Cell Line, Tumor; Colonic Neoplasms; Female; Male; Melanoma; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Programmed Cell Death 1 Receptor
PubMed: 31901074
DOI: 10.1126/sciimmunol.aay1863 -
Immunity Aug 2020Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes....
Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes. Although studies have proposed lineage heterogeneity within GMPs, it is unclear if committed progenitors already exist among these progenitors and how they may behave differently during inflammation. By combining single-cell transcriptomic and proteomic analyses, we identified the early committed progenitor within the GMPs responsible for the strict production of neutrophils, which we designate as proNeu1. Our dissection of the GMP hierarchy led us to further identify a previously unknown intermediate proNeu2 population. Similar populations could be detected in human samples. proNeu1s, but not proNeu2s, selectively expanded during the early phase of sepsis at the expense of monocytes. Collectively, our findings help shape the neutrophil maturation trajectory roadmap and challenge the current definition of GMPs.
Topics: Animals; Granulocyte Precursor Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Myelopoiesis; Neutrophils; Single-Cell Analysis
PubMed: 32579887
DOI: 10.1016/j.immuni.2020.06.005 -
Cell Stem Cell May 2023Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain...
Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitor (OP) expansion, hematopoietic stem cell dislocation, and CD41 granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41 GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in the hematopoietic program. Importantly, these effects persist post-surgery and continue to impair anti-tumor immunity. Conditional knockout or inhibition of MMP-13 accelerates immune reinstatement and restores the efficacies of immunotherapies. Therefore, tumor-induced systemic effects are initiated by OP-GMP crosstalk that outlasts tumor burden, and additional treatment is required to reverse these effects for optimal therapeutic efficacy.
Topics: Humans; Matrix Metalloproteinase 13; Ecosystem; Myelopoiesis; Hematopoietic Stem Cells; Neoplasms; Immunosuppression Therapy; High-Temperature Requirement A Serine Peptidase 1
PubMed: 37146584
DOI: 10.1016/j.stem.2023.04.005 -
Acta Haematologica 2019Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending,... (Review)
Review
Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending, morphology supplemented by immunophenotyping can provide clues to the diagnosis of specific cytogenetic/genetic categories of AML. Most importantly, acute promyelocytic leukaemia can be diagnosed with a high degree of certainty. However, provisional identification of cases associated with t(8; 21), inv(16), t(1; 22), and NPM1 mutation may also be possible. In addition, transient abnormal myelopoiesis of Down's syndrome can generally be diagnosed morphologically.
Topics: Chromosome Inversion; Chromosomes, Human; Down Syndrome; Humans; Leukemia, Promyelocytic, Acute; Myelopoiesis; Neoplasm Proteins; Nuclear Proteins; Nucleophosmin; Translocation, Genetic; World Health Organization
PubMed: 30965338
DOI: 10.1159/000496097 -
Circulation Mar 2020Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and...
BACKGROUND
Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.
METHODS
Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI.
RESULTS
Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes.
CONCLUSIONS
Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.
Topics: Animals; Calgranulin A; Disease Models, Animal; Female; Granulocytes; Humans; Male; Mice; Myocardial Infarction; Neutrophils
PubMed: 31941367
DOI: 10.1161/CIRCULATIONAHA.119.043833 -
Cell Stem Cell May 2020Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain...
Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. We show that acute immune stimulation with lipopolysaccharide (LPS) induced only transient changes in HSC abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. Functionally, this was associated with increased myelopoiesis of pre-exposed HSCs and improved innate immunity against the gram-negative bacterium P. aeruginosa. The accessible myeloid enhancers were enriched for C/EBPβ targets, and C/EBPβ deletion erased the long-term inscription of LPS-induced epigenetic marks and gene expression. Thus, short-term immune signaling can induce C/EBPβ-dependent chromatin accessibility, resulting in HSC-trained immunity, during secondary infection. This establishes a mechanism for how infection history can be epigenetically inscribed in HSCs as an integral memory function of innate immunity.
Topics: CCAAT-Enhancer-Binding Protein-beta; Epigenesis, Genetic; Epigenomics; Hematopoietic Stem Cells; Humans; Immunity, Innate; Myelopoiesis
PubMed: 32169166
DOI: 10.1016/j.stem.2020.01.017