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1.
Methods Cell Biol ; 174: 17-30, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36710048

RESUMO

The use of ionizing radiation (IR) is a cornerstone for the treatment of cancer and radiotherapy (RT) is used in roughly 50% of cancer patients. It is now well established that RT exerts widespread effects on the tumor stroma, including the immune environment. Together with its deeply characterized effects on the lymphoid compartment, RT also deeply affects the myeloid cell compartment. Fluorescence-activated flow cytometry is one of the most widely used technologies in immunology, allowing the multiparametric analysis of cells on a cell-by-cell basis. Here, we provide a detailed flow cytometry protocol to analyze the myeloid cell populations of human papillomavirus (HPV)-positive TC1/Luc tumors engrafted in the oral mucosa of immunocompetent mice, and to evaluate their modulations in response to RT. The same method, with slight modifications, can be used to study the tumor myeloid cells from a variety of other mouse tumors.


Assuntos
Células Mieloides , Neoplasias , Animais , Humanos , Camundongos , Neoplasias/radioterapia , Radiação Ionizante , Células Mieloides/efeitos da radiação , Citometria de Fluxo
2.
Science ; 379(6627): 28-29, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36603093
3.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36650020

RESUMO

BACKGROUND: Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment. METHODS: We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models. RESULTS: Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo. CONCLUSION: Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.


Assuntos
Reabsorção Óssea , Mieloma Múltiplo , Quinolonas , Animais , Camundongos , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Proliferação de Células , Imunossupressores/farmacologia , Mieloma Múltiplo/patologia , Células Mieloides/metabolismo , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Quinolonas/metabolismo , Microambiente Tumoral , Humanos
4.
Sci Signal ; 16(768): eabh1083, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36649377

RESUMO

Inflammasomes are intracellular protein complexes that promote an inflammatory host defense in response to pathogens and damaged or neoplastic tissues and are implicated in inflammatory disorders and therapeutic-induced toxicity. We investigated the mechanisms of activation for inflammasomes nucleated by NOD-like receptor (NLR) protiens. A screen of a small-molecule library revealed that several tyrosine kinase inhibitors (TKIs)-including those that are clinically approved (such as imatinib and crizotinib) or are in clinical trials (such as masitinib)-activated the NLRP3 inflammasome. Furthermore, imatinib and masitinib caused lysosomal swelling and damage independently of their kinase target, leading to cathepsin-mediated destabilization of myeloid cell membranes and, ultimately, cell lysis that was accompanied by potassium (K+) efflux, which activated NLRP3. This effect was specific to primary myeloid cells (such as peripheral blood mononuclear cells and mouse bone marrow-derived dendritic cells) and did not occur in other primary cell types or various cell lines. TKI-induced lytic cell death and NLRP3 activation, but not lysosomal damage, were prevented by stabilizing cell membranes. Our findings reveal a potential immunological off-target of some TKIs that may contribute to their clinical efficacy or to their adverse effects.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mesilato de Imatinib , Leucócitos Mononucleares/metabolismo , Morte Celular , Células Mieloides/metabolismo , Interleucina-1beta/metabolismo
6.
Dis Model Mech ; 16(2)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36645087

RESUMO

PTPN6 encodes SHP1, a protein tyrosine phosphatase with an essential role in immune cell function. SHP1 mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in motheaten mice that lack functional SHP1. To investigate the function of Shp1 in developing zebrafish embryos, we generated a ptpn6 knockout zebrafish line lacking functional Shp1. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). During early development, the myeloid lineage was affected, resulting in a decrease in the number of neutrophils and a concomitant increase in the number of macrophages. The number of emerging hematopoietic stem and progenitor cells (HSPCs) was decreased, but due to hyperproliferation, the number of HSPCs was higher in ptpn6 mutants than in siblings at 5 dpf. Finally, the directional migration of neutrophils and macrophages was decreased in response to wounding, and fewer macrophages were recruited to the wound site. Yet, regeneration of the caudal fin fold was normal. We conclude that loss of Shp1 impaired neutrophil and macrophage function, and caused severe inflammation and lethality at the larval stage.


Assuntos
Inflamação , Peixe-Zebra , Humanos , Camundongos , Animais , Peixe-Zebra/metabolismo , Inflamação/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Células Mieloides/metabolismo
7.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36627143

RESUMO

BACKGROUND: Microphthalmia-associated transcription factor (MITF) is a master regulator of melanogenesis and is mainly expressed in melanoma cells. MITF has also been reported to be expressed in non-pigmented cells, such as osteoclasts, mast cells, and B cells. However, the roles of MITF in immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), remain unclear. Here, we investigated the role of MITF in the differentiation process of MDSCs during tumor development. METHODS: In vitro-generated murine MDSCs and primary MDSCs from breast cancer-bearing mice or lung carcinoma-bearing mice were used to determine the expression level of MITF and the activity of MDSCs. Additionally, we investigated whether in vivo tumor growth can be differentially regulated by coinjection of MDSCs in which MITF expression is modulated by small molecules. Furthermore, the number of MITF+ monocytic (MO)-MDSCs was examined in human tumor tissues or tumor-free lymph nodes by immunohistochemistry (IHC). RESULTS: The expression of MITF was strongly increased in MO-MDSCs from tumors of breast cancer-bearing mice compared with polymorphonuclear MDSCs. We found that MITF expression in MDSCs was markedly induced in the tumor microenvironment (TME) and related to the functional activity of MDSCs. MITF overexpression in myeloid cells increased the expression of MDSC activity markers and effectively inhibited T-cell proliferation compared with those of control MDSCs, whereas shRNA-mediated knockdown of MITF in myeloid cells altered the immunosuppressive function of MDSCs. Modulation of MITF expression by small molecules affected the differentiation and immunosuppressive function of MDSCs. While increased MITF expression in MDSCs promoted breast cancer progression and CD4+ or CD8+ T-cell dysfunction, decreased MITF expression in MDSCs suppressed tumor progression and enhanced T-cell activation. Furthermore, IHC staining of human tumor tissues revealed that MITF+ MO-MDSCs are more frequently observed in tumor tissues than in tumor-free draining lymph nodes obtained from patients with cancer. CONCLUSIONS: Our results indicate that MITF regulates the differentiation and function of MDSCs and can be a novel therapeutic target for modulating MDSC activity in immunosuppressive s.


Assuntos
Neoplasias da Mama , Fator de Transcrição Associado à Microftalmia , Células Supressoras Mieloides , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/patologia , Diferenciação Celular , Fator de Transcrição Associado à Microftalmia/genética , Células Mieloides/metabolismo , Células Supressoras Mieloides/metabolismo , Microambiente Tumoral
8.
Sci Rep ; 13(1): 482, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627355

RESUMO

Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) is a membrane protein expressed on immune cells, involved in neurodegenerative diseases and cancer. Recently, it was shown that TREM2 is expressed on lipid associated macrophages in adipose tissue, and that TREM2 knockout mice suffer from metabolic symptoms. Here, a computational study using public databases, brings direct evidence for the involvement of TREM2 in human obesity. First, we show a significant correlation between TREM2 expression levels and BMI in adipose tissues in samples from the GTEx database. This association was evident for males but not for females. Second, we identified in the UK Biobank cohort a coding SNP in TREM2 with a significant effect on BMI. Compared to previously identified SNPs associated with BMI, this SNP (rs2234256 SNP, L211P) has the strongest association, reflected in significantly higher BMI values of people carrying the SNP as heterozygous and even more for homozygous. Strikingly, this association was evident only for females. These observations suggest a novel gender-specific role of TREM2 in human obesity, and call for further studies to elucidate the mechanism by which this gene correlates with an obese phenotype.


Assuntos
Glicoproteínas de Membrana , Obesidade , Receptores Imunológicos , Feminino , Humanos , Masculino , Tecido Adiposo/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Células Mieloides/metabolismo , Obesidade/genética , Obesidade/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
9.
Nat Cancer ; 4(1): 62-80, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36585453

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Células Mieloides/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
10.
Nat Immunol ; 24(1): 55-68, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36581713

RESUMO

The inhibitory receptor PD-1 suppresses T cell activation by recruiting the phosphatase SHP-2. However, mice with a T-cell-specific deletion of SHP-2 do not have improved antitumor immunity. Here we showed that mice with conditional targeting of SHP-2 in myeloid cells, but not in T cells, had diminished tumor growth. RNA sequencing (RNA-seq) followed by gene set enrichment analysis indicated the presence of polymorphonuclear myeloid-derived suppressor cells and tumor-associated macrophages (TAMs) with enriched gene expression profiles of enhanced differentiation, activation and expression of immunostimulatory molecules. In mice with conditional targeting of PD-1 in myeloid cells, which also displayed diminished tumor growth, TAMs had gene expression profiles enriched for myeloid differentiation, activation and leukocyte-mediated immunity displaying >50% overlap with enriched profiles of SHP-2-deficient TAMs. In bone marrow, GM-CSF induced the phosphorylation of PD-1 and recruitment of PD-1-SHP-2 to the GM-CSF receptor. Deletion of SHP-2 or PD-1 enhanced GM-CSF-mediated phosphorylation of the transcription factors HOXA10 and IRF8, which regulate myeloid differentiation and monocytic-moDC lineage commitment, respectively. Thus, SHP-2 and PD-1-SHP-2 signaling restrained myelocyte differentiation resulting in a myeloid landscape that suppressed antitumor immunity.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Neoplasias , Animais , Camundongos , Diferenciação Celular , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Células Mieloides , Receptor de Morte Celular Programada 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6 , Transdução de Sinais
11.
J Neuroimmunol ; 374: 578009, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36508930

RESUMO

Central nervous system (CNS) tumors are the most common type of solid tumors in children and the leading cause of cancer deaths in ages 0-14. Recent advances in the field of tumor biology and immunology have underscored the disparate nature of these distinct CNS tumor types. In this review, we briefly introduce pediatric CNS tumors and discuss various components of the TME, with a particular focus on myeloid cells. Although most studies regarding myeloid cells have been done on adult CNS tumors and animal models, we discuss the role of myeloid cell heterogeneity in pediatric CNS tumors and describe how these cells may contribute to tumorigenesis and treatment response. In addition, we present studies within the last 5 years that highlight human CNS tumors, the utility of various murine CNS tumor models, and the latest multi-dimensional tools that can be leveraged to investigate myeloid cell infiltration in young adults and children diagnosed with select CNS tumors.


Assuntos
Neoplasias do Sistema Nervoso Central , Microambiente Tumoral , Criança , Humanos , Animais , Camundongos , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Neoplasias do Sistema Nervoso Central/terapia , Sistema Nervoso Central/patologia , Células Mieloides/metabolismo
12.
Front Immunol ; 13: 1050484, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36458011

RESUMO

Dendritic cells (DCs) are a heterogenous population of professional antigen presenting cells whose main role is diminished in a variety of malignancies, including cancer, leading to ineffective immune responses. Those mechanisms are inhibited due to the immunosuppressive conditions found in the tumor microenvironment (TME), where myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells known to play a key role in tumor immunoevasion by inhibiting T-cell responses, are extremely accumulated. In addition, it has been demonstrated that MDSCs not only suppress DC functions, but also their maturation and development within the myeloid linage. Considering that an increased number of DCs as well as the improvement in their functions boost antitumor immunity, DC-based vaccines were developed two decades ago, and promising results have been obtained throughout these years. Therefore, the remodeling of the TME promoted by DC vaccination has also been explored. Here, we aim to review the effectiveness of different DCs-based vaccines in murine models and cancer patients, either alone or synergistically combined with other treatments, being especially focused on their effect on the MDSC population.


Assuntos
Células Supressoras Mieloides , Neoplasias , Humanos , Animais , Camundongos , Microambiente Tumoral , Neoplasias/terapia , Células Mieloides , Células Dendríticas
13.
Nat Commun ; 13(1): 7657, 2022 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-36496394

RESUMO

Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas , Camundongos , Animais , Células-Tronco Hematopoéticas/metabolismo , Células Mieloides , Medula Óssea/fisiologia , Interferons/metabolismo , Diferenciação Celular , Mamíferos
14.
Nat Commun ; 13(1): 7634, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36496458

RESUMO

Knowledge of the transcriptional programs underpinning the functions of human kidney cell populations at homeostasis is limited. We present a single-cell perspective of healthy human kidney from 19 living donors, with equal contribution from males and females, profiling the transcriptome of 27677 cells to map human kidney at high resolution. Sex-based differences in gene expression within proximal tubular cells were observed, specifically, increased anti-oxidant metallothionein genes in females and aerobic metabolism-related genes in males. Functional differences in metabolism were confirmed in proximal tubular cells, with male cells exhibiting higher oxidative phosphorylation and higher levels of energy precursor metabolites. We identified kidney-specific lymphocyte populations with unique transcriptional profiles indicative of kidney-adapted functions. Significant heterogeneity in myeloid cells was observed, with a MRC1+LYVE1+FOLR2+C1QC+ population representing a predominant population in healthy kidney. This study provides a detailed cellular map of healthy human kidney, and explores the complexity of parenchymal and kidney-resident immune cells.


Assuntos
Receptor 2 de Folato , Rim , Feminino , Humanos , Masculino , Rim/metabolismo , Transcriptoma , Metalotioneína/genética , Metalotioneína/metabolismo , Células Mieloides/metabolismo , Perfilação da Expressão Gênica , Análise de Célula Única , Receptor 2 de Folato/metabolismo
15.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36555456

RESUMO

Myocardial infarction (MI), a major contributor to worldwide morbidity and mortality, is caused by a lack of blood flow to the heart. Affected heart tissue becomes ischemic due to deficiency of blood perfusion and oxygen delivery. In case sufficient blood flow cannot be timely restored, cardiac injury with necrosis occurs. The ischemic/necrotic area induces a systemic inflammatory response and hundreds of thousands of leukocytes are recruited from the blood to the injured heart. The blood pool of leukocytes is rapidly depleted and urgent re-supply of these cells is needed. Myeloid cells are generated in the bone marrow (BM) and spleen, released into the blood, travel to sites of need, extravasate and accumulate inside tissues to accomplish various functions. In this review we focus on the "leukocyte supply chain" and will separately evaluate different myeloid cell compartments (BM, spleen, blood, heart) in steady state and after MI. Moreover, we highlight the local and systemic kinetics of extracellular factors, chemokines and danger signals involved in the regulation of production/generation, release, transportation, uptake, and activation of myeloid cells during the inflammatory phase of MI.


Assuntos
Infarto do Miocárdio , Humanos , Células Mieloides , Leucócitos , Necrose , Baço
16.
Sci Immunol ; 7(78): eade5728, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36525507

RESUMO

Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL-37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, here we show that the longest IL-37 isoform, IL-37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1ß. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53-truncated form of IL-37, mimicking the cathepsin S-processed form of this cytokine, was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R-/- animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases.


Assuntos
Interleucina-1 , Peptídeo Hidrolases , Receptores de Interleucina , Animais , Camundongos , Caspases , Catepsinas , Citocinas , Interleucina-1/metabolismo , Células Mieloides , Receptores de Interleucina/metabolismo
17.
Cells ; 11(24)2022 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-36552868

RESUMO

Aberrant expression of the oncoprotein c-Myc (Myc) is frequently observed in solid tumors and is associated with reduced overall survival. In addition to well-recognized cancer cell-intrinsic roles of Myc, studies have also suggested tumor-promoting roles for Myc in cells of the tumor microenvironment, including macrophages and other myeloid cells. Here, we benchmark Myc inactivation in tumor cells against the contribution of its expression in myeloid cells of murine hosts that harbor endogenous or allograft tumors. Surprisingly, we observe that LysMCre-mediated Myc ablation in host macrophages does not attenuate tumor growth regardless of immunogenicity, the cellular origin of the tumor, the site it develops, or the stage along the tumor progression cascade. Likewise, we find no evidence for Myc ablation to revert or antagonize the polarization of alternatively activated immunosuppressive macrophages. Thus, we surmise that systemic targeting of Myc activity may confer therapeutic benefits primarily through limiting Myc activity in tumor cells rather than reinvigorating the anti-tumor activity of macrophages.


Assuntos
Macrófagos , Neoplasias , Camundongos , Animais , Macrófagos/metabolismo , Neoplasias/metabolismo , Células Mieloides/metabolismo , Microambiente Tumoral
18.
Front Immunol ; 13: 1071188, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36532078

RESUMO

The leukemic microenvironment has a high diversity of immune cells that are phenotypically and functionally distinct. However, our understanding of the biology, immunology, and clinical implications underlying these cells remains poorly investigated. Among the resident immune cells that can infiltrate the leukemic microenvironment are myeloid cells, which correspond to a heterogeneous cell group of the innate immune system. They encompass populations of neutrophils, macrophages, and myeloid-derived suppressor cells (MDSCs). These cells can be abundant in different tissues and, in the leukemic microenvironment, are associated with the clinical outcome of the patient, acting dichotomously to contribute to leukemic progression or stimulate antitumor immune responses. In this review, we detail the current evidence and the many mechanisms that indicate that the activation of different myeloid cell populations may contribute to immunosuppression, survival, or metastatic dissemination, as well as in immunosurveillance and stimulation of specific cytotoxic responses. Furthermore, we broadly discuss the interactions of tumor-associated neutrophils and macrophages (TANs and TAMs, respectively) and MDSCs in the leukemic microenvironment. Finally, we provide new perspectives on the potential of myeloid cell subpopulations as predictive biomarkers of therapeutical response, as well as potential targets in the chemoimmunotherapy of leukemias due to their dual Yin-Yang roles in leukemia.


Assuntos
Células Supressoras Mieloides , Microambiente Tumoral , Humanos , Yin-Yang , Células Mieloides , Imunoterapia
19.
Am J Manag Care ; 28(16 Suppl): S323-S328, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36548523

RESUMO

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative condition that results in progressive accumulation of disability over the course of the disease. MS presents heterogeneously, and, as the disease progresses, patients develop a range of physical and neurologic problems that include reduced mobility, cognitive impairment, weakness, fatigue, pain, and defects in speech or vision. Economically, MS is costly, including both direct costs stemming from clinical care and medications and the indirect costs of productivity losses. These costs pose a substantial burden to patients, families, caregivers, employers, and society. There are 21 approved disease-modifying therapies for MS across several drug classes. The importance of early MS treatment has been confirmed, and progress has been made in the treatment of relapsing-remitting MS, although this progress has not been replicated for progressive presentations of the disease. Ongoing research continues to elucidate the exact mechanisms of disease in MS as well as potential new treatment strategies that may better address current gaps, such as disability progression in secondary progressive MS without activity. One of the novel pathways under investigation is the inhibition of Bruton tyrosine kinase, a cytoplasmic tyrosine kinase, which is expressed in B cells and other potentially targetable hematopoietic lineage cells. This review examines emerging hypotheses that targeting both B cells and myeloid cells within the periphery and central nervous system could yield clinical effects in key areas of MS pathophysiology that are currently unaddressed.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Esclerose Múltipla , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/enzimologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/enzimologia , Redes e Vias Metabólicas , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Células Mieloides/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
20.
Front Immunol ; 13: 1003975, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36531986

RESUMO

Junctional adhesion molecule-A (JAM-A), expressed on the surface of myeloid cells, is required for extravasation at sites of inflammation and may also modulate myeloid cell activation. Infiltration of myeloid cells is a common feature of tumors that drives disease progression, but the function of JAM-A in this phenomenon and its impact on tumor-infiltrating myeloid cells is little understood. Here we show that systemic cancer-associated inflammation in mice enhanced JAM-A expression selectively on circulating monocytes in an IL1ß-dependent manner. Using myeloid-specific JAM-A-deficient mice, we found that JAM-A was dispensable for recruitment of monocytes and other myeloid cells to tumors, in contrast to its reported role in inflammation. Single-cell RNA sequencing revealed that loss of JAM-A did not influence the transcriptional reprogramming of myeloid cells in the tumor microenvironment. Overall, our results support the notion that cancer-associated inflammation can modulate the phenotype of circulating immune cells, and we demonstrate that tumors can bypass the requirement of JAM-A for myeloid cell recruitment and reprogramming.


Assuntos
Molécula A de Adesão Juncional , Camundongos , Animais , Microambiente Tumoral/genética , Células Mieloides/metabolismo , Monócitos/metabolismo , Inflamação/metabolismo
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