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1.
Immunity ; 48(1): 91-106.e6, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29343444

RESUMO

CD103+ dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c+ monocytic precursors. These Ly6c+CD103+ cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c+CD103+ phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6c+CD103+ population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6c+CD103+ cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6c+CD103+ monocytic cells represents a potent and previously unrecognized target for immunotherapy.


Assuntos
Células Apresentadoras de Antígenos/fisiologia , Monócitos/fisiologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos CD/metabolismo , Antígenos Ly/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular , Citometria de Fluxo , Humanos , Imunoterapia/métodos , Cadeias alfa de Integrinas/metabolismo , Camundongos , Monócitos/imunologia , Células Mieloides/fisiologia
2.
Proc Natl Acad Sci U S A ; 121(5): e2318534121, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38261615

RESUMO

The use of colony-stimulating factor-1 receptor (CSF1R) inhibitors has been widely explored as a strategy for cancer immunotherapy due to their robust depletion of tumor-associated macrophages (TAMs). While CSF1R blockade effectively eliminates TAMs from the solid tumor microenvironment, its clinical efficacy is limited. Here, we use an inducible CSF1R knockout model to investigate the persistence of tumor progression in the absence of TAMs. We find increased frequencies of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the bone marrow, throughout circulation, and in the tumor following CSF1R deletion and loss of TAMs. We find that G-MDSCs are capable of suppressing macrophage phagocytosis, and the elimination of G-MDSCs through CXCR2 inhibition increases macrophage capacity for tumor cell clearance. Further, we find that combination therapy of CXCR2 inhibition and CD47 blockade synergize to elicit a significant anti-tumor response. These findings reveal G-MDSCs as key drivers of tumor immunosuppression and demonstrate their inhibition as a potent strategy to increase macrophage phagocytosis and enhance the anti-tumor efficacy of CD47 blockade in B16-F10 melanoma.


Assuntos
Melanoma Experimental , Células Supressoras Mieloides , Animais , Antígeno CD47 , Granulócitos , Macrófagos , Microambiente Tumoral , Camundongos
3.
Proc Natl Acad Sci U S A ; 121(20): e2306776121, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38709933

RESUMO

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.


Assuntos
Neoplasias da Mama , Diferenciação Celular , Dieta Hiperlipídica , Progressão da Doença , Microbioma Gastrointestinal , Leucina , Células Supressoras Mieloides , Animais , Dieta Hiperlipídica/efeitos adversos , Leucina/metabolismo , Feminino , Humanos , Camundongos , Células Supressoras Mieloides/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/microbiologia , Neoplasias da Mama/metabolismo , Obesidade/microbiologia , Obesidade/metabolismo , Obesidade/patologia , Linhagem Celular Tumoral
4.
Immunol Rev ; 314(1): 13-35, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36527200

RESUMO

Neutrophils sense microbes and host inflammatory mediators, and traffic to sites of infection where they direct a broad armamentarium of antimicrobial products against pathogens. Neutrophils are also activated by damage-associated molecular patterns (DAMPs), which are products of cellular injury that stimulate the innate immune system through pathways that are similar to those activated by microbes. Neutrophils and platelets become activated by injury, and cluster and cross-signal to each other with the cumulative effect of driving antimicrobial defense and hemostasis. In addition, neutrophil extracellular traps are extracellular chromatin and granular constituents that are generated in response to microbial and damage motifs and are pro-thrombotic and injurious. Although neutrophils can worsen tissue injury, neutrophils may also have a role in facilitating wound repair following injury. A central theme of this review relates to how critical functions of neutrophils that evolved to respond to infection and damage modulate the tumor microenvironment (TME) in ways that can promote or limit tumor progression. Neutrophils are reprogrammed by the TME, and, in turn, can cross-signal to tumor cells and reshape the immune landscape of tumors. Importantly, promising new therapeutic strategies have been developed to target neutrophil recruitment and function to make cancer immunotherapy more effective.


Assuntos
Armadilhas Extracelulares , Neutrófilos , Humanos , Plaquetas/metabolismo , Plaquetas/patologia , Células Endoteliais , Inflamação , Linfócitos T , Armadilhas Extracelulares/metabolismo
5.
Semin Immunol ; 61-64: 101668, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36370673

RESUMO

Human myeloid-derived suppressor cells (MDSC) represent a stage of immature myeloid cells and two main subsets can be identified: monocytic and polymorphonuclear. MDSC contribute to the establishment of an immunosuppressive tumor microenvironment (TME). The presence and the activity of MDSC in patients with different tumors correlate with poor prognosis. As previously reported, MDSC promote tumor growth and use different mechanisms to suppress the immune cell-mediated anti-tumor activity. Immunosuppression mechanisms used by MDSC are broad and depend on their differentiation stage and on the pathological context. It is known that some effector cells of the immune system can play an important role in the control of tumor progression and metastatic spread. In particular, innate lymphoid cells (ILC) contribute to control tumor growth representing a potential, versatile and, immunotherapeutic tool. Despite promising results obtained by using new cellular immunotherapeutic approaches, a relevant proportion of patients do not benefit from these therapies. Novel strategies have been investigated to overcome the detrimental effect exerted by the immunosuppressive component of TME (i.e. MDSC). In this review, we summarized the characteristics and the interactions occurring between MDSC and ILC in different tumors discussing how a deeper knowledge on MDSC biology could represent an important target for tumor immunotherapy capable of decreasing immunosuppression and enhancing anti-tumor activity exerted by immune cells.


Assuntos
Células Supressoras Mieloides , Neoplasias , Humanos , Imunidade Inata , Linfócitos/patologia , Microambiente Tumoral
6.
Eur J Immunol ; : e2350823, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38922875

RESUMO

Osteoclast-mediated bone erosion and deformation represent significant pathological features in rheumatoid arthritis (RA). Myeloid-derived suppressor cells (MDSCs) and B cells have emerged as key contributors to the progression of RA. Nevertheless, their involvement, especially the interaction in RA osteoclastogenesis remains elusive. In this study, our results revealed a marked expansion of MDSCs in RA patients, and importantly, their abundance was positively correlated with radiographic damage evaluated by the Sharp/van der Heijde score. Notably, MDSCs derived from both RA patients and arthritic mice exhibited a heightened propensity to differentiate into osteoclasts compared with those from healthy individuals. Intriguingly, we observed that B cells from RA patients could augment the osteoclastogenic potential of MDSCs, which was also observed in arthritic mice. The impact of B cells on MDSC-mediated osteoclastogenesis was found to be most pronounced in switched memory B cells, followed by CD21low B cells and naïve B cells. MDSCs from B-cell-deficient mice exhibited diminished capacity to differentiate into osteoclasts, accompanied by distinct gene expression profiles associated with osteoclastogenesis. Taken together, our findings suggested that MDSCs were important osteoclast precursors primed by B cells in RA, serving as novel therapeutic targets for the persistent disease.

7.
Eur J Immunol ; 54(7): e2350785, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38654479

RESUMO

Myeloid-derived suppressor cells (MDSCs) hold promise for clinical applications due to their immunosuppressive properties, particularly in the context of inflammation. In the present study, the number and immunosuppressive activity of MDSCs isolated from naïve Il10-/-, Il17-/-, and WT mice as control, as well as from house dust mite extract (HDM)-induced asthmatic Il10-/- and Il17-/- mice, were investigated. IL-10 deficiency increased the number of polymorphonuclear (PMN)-MDSCs in the lung, spleen, and bone marrow, without concurrent impairment of their suppressive activity in vitro. In the asthma model, the IL-17 knockout was concomitant with a lower number and activity of monocytic (M)-MDSCs and an altered inflammatory reaction with impaired lung function. Additionally, we found a higher baseline inflammation of the Il17-/- mice in the lung, manifested in increased airway resistance. We conclude that the impact of IL-10 and IL-17 deficiency on MDSCs differs in the context of inflammation. Accordingly, the in vitro experiments demonstrated an increased number of PMN-MDSCs across tissues in Il10-/- mice, which indicates that IL-10 might serve a pivotal role in preserving immune homeostasis under physiological circumstances. In the context of HDM-induced airway inflammation, IL-17 was found to be an important player in the suppression of pulmonary inflammation and regulation of M-MDSCs.


Assuntos
Asma , Modelos Animais de Doenças , Interleucina-10 , Interleucina-17 , Células Supressoras Mieloides , Animais , Camundongos , Asma/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Pyroglyphidae/imunologia
8.
FASEB J ; 38(1): e23338, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38038723

RESUMO

Tristetraprolin (TTP; also known as NUP475, GOS24, or TIS11), encoded by Zfp36, is an RNA-binding protein that regulates target gene expression by promoting mRNA decay and preventing translation. Although previous studies have indicated that TTP deficiency is associated with systemic inflammation and a catabolic-like skeletal phenotype, the mechanistic underpinnings remain unclear. Here, using both TTP-deficient (TTPKO) and myeloid-specific TTPKO (cTTPKO) mice, we reveal that global absence or loss of TTP in the myeloid compartment results in a reduced bone microarchitecture, whereas gain-of-function TTP knock-in (TTPKI) mice exhibit no significant loss of bone microarchitecture. Flow cytometry analysis revealed a significant immunosuppressive immune cell phenotype with increased monocytic myeloid-derived suppressor cells (M-MDSCs) in TTPKO and cTTPKO mice, whereas no significant changes were observed in TTPKI mice. Single-cell transcriptomic analyses of bone marrow myeloid progenitor cell populations indicated a dramatic increase in early MDSC marker genes for both cTTPKO and TTPKO bone marrow populations. Consistent with these phenotypic and transcriptomic data, in vitro osteoclastogenesis analysis of bone marrow M-MDSCs from cTTPKO and TTPKO displayed enhanced osteoclast differentiation and functional capacity. Focused transcriptomic analyses of differentiated M-MDSCs showed increased osteoclast-specific transcription factors and cell fusion gene expression. Finally, functional data showed that M-MDSCs from TTP loss-of-function mice were capable of osteoclastogenesis and bone resorption in a context-dependent manner. Collectively, these findings indicate that TTP plays a central role in regulating osteoclastogenesis through multiple mechanisms, including induction of M-MDSCs that appear to regulate skeletal phenotype.


Assuntos
Células Supressoras Mieloides , Tristetraprolina , Animais , Camundongos , Osteoclastos/metabolismo , Osteogênese , Fenótipo , Tristetraprolina/genética
9.
EMBO Rep ; 24(3): e55328, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36715148

RESUMO

The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial-derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol-25-hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well-understood. Using floxed-reporter Ch25h knock-in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h-deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h-deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations.


Assuntos
Encefalomielite Autoimune Experimental , Oxisteróis , Camundongos , Animais , Células Endoteliais/metabolismo , Oxisteróis/metabolismo , Doenças Neuroinflamatórias , Sistema Nervoso Central/metabolismo , Camundongos Endogâmicos C57BL
10.
EMBO Rep ; 24(4): e56524, 2023 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-36802267

RESUMO

We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the KrasG12D mutation and drives tumoral growth in vitro and in vivo. We term these cells pericyte stem cells (PeSCs) and define them as CD45- EPCAM- CD29+ CD106+ CD24+ CD44+ cells. We perform studies with p48-Cre;KrasG12D (KC), pdx1-Cre;KrasG12D ;Ink4a/Arffl/fl (KIC) and pdx1-Cre;KrasG12D ;p53R172H (KPC) and tumor tissues from PDAC and chronic pancreatitis patients. We also perform single-cell RNAseq analysis and reveal a unique signature of PeSC. Under steady-state conditions, PeSCs are barely detectable in the pancreas but present in the neoplastic microenvironment both in humans and mice. The coinjection of PeSCs and tumor epithelial cells leads to increased tumor growth, differentiation of Ly6G+ myeloid-derived suppressor cells, and a decreased amount of F4/80+ macrophages and CD11c+ dendritic cells. This population induces resistance to anti-PD-1 immunotherapy when coinjected with epithelial tumor cells. Our data reveal the existence of a cell population that instructs immunosuppressive myeloid cell responses to bypass PD-1 targeting and thus suggest potential new approaches for overcoming resistance to immunotherapy in clinical settings.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/genética , Pericitos , Proteínas Proto-Oncogênicas p21(ras) , Células-Tronco , Microambiente Tumoral , Neoplasias Pancreáticas
11.
Mol Cell Proteomics ; 22(9): 100632, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37586548

RESUMO

Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population of incompletely differentiated immune cells. They are known to suppress T cell activity and are implicated in multiple chronic diseases, which make them an attractive cell population for drug discovery. Here, we characterized the baseline proteomes and phospho-proteomes of mouse MDSC differentiated from a progenitor cell line to a depth of 7000 proteins and phosphorylation sites. We also validated the cellular system for drug discovery by recapitulating and identifying known and novel molecular responses to the well-studied MDSC drugs entinostat and mocetinostat. We established a high-throughput drug screening platform using a MDSC/T cell coculture system and assessed the effects of ∼21,000 small molecule compounds on T cell proliferation and IFN-γ secretion to identify novel MDSC modulator. The most promising candidates were validated in a human MDSC system, and subsequent proteomic experiments showed significant upregulation of several proteins associated with the reduction of reactive oxygen species (ROS). Proteome-wide solvent-induced protein stability assays identified Acyp1 and Cd74 as potential targets, and the ROS-reducing drug phenotype was validated by measuring ROS levels in cells in response to compound, suggesting a potential mode of action. We anticipate that the data and chemical tools developed in this study will be valuable for further research on MDSC and related drug discovery.


Assuntos
Células Supressoras Mieloides , Camundongos , Humanos , Animais , Células Supressoras Mieloides/metabolismo , Ensaios de Triagem em Larga Escala , Proteoma/metabolismo , Proteômica , Espécies Reativas de Oxigênio/metabolismo
12.
Semin Immunol ; 57: 101582, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34974960

RESUMO

For the past decade, the role and importance of neutrophils in cancer is being increasingly appreciated. Research has focused on the ability of cancer-related neutrophils to either support tumor growth or interfere with it, showing diverse mechanisms through which the effects of neutrophils take place. In contrast to the historic view of neutrophils as terminally differentiated cells, mounting evidence has demonstrated that neutrophils are a plastic and diverse population of cells. These dynamic and plastic abilities allow them to perform varied and sometimes opposite functions simultaneously. In this review, we summarize and detail clinical and experimental evidence for, and underlying mechanisms of, the dual impact of neutrophils' functions, both supporting and inhibiting cancer development. We first discuss the effects of various basic functions of neutrophils, namely direct cytotoxicity, secretion of reactive oxygen species (ROS), nitric oxide (NO) and proteases, NETosis, autophagy and modulation of other immune cells, on tumor growth and metastatic progression. We then describe the clinical evidence for pro- vs anti-tumor functions of neutrophils in human cancer. We believe and show that the "net" impact of neutrophils in cancer is the sum of a complex balance between contradicting effects which occur simultaneously.


Assuntos
Neoplasias , Neutrófilos , Humanos , Plásticos , Espécies Reativas de Oxigênio , Microambiente Tumoral
13.
Immunology ; 172(2): 252-268, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38424694

RESUMO

Vaccination after birth provides protection against pathogen infection and immune related disorders in healthy children. The detailed effects of vaccination on neonatal immunity, however, remain largely unknown. Here, we reported that vaccination using Bacillus Calmette-Guérin (BCG) diminished the immunosuppressive function of myeloid-derived suppressor cells in neonatal mice, an immature myeloid population. A combination of single-cell transcriptome, metabolite profiling, and functional analysis demonstrated that upregulation of mTOR/HIF1a signalling and the enhanced glycolysis explained the effects of BCG on neonatal myeloid cells. Pharmalogical inhibition of glycolysis or mTOR signalling efficiently rescued the effects of BCG on neonatal myeloid cells. These observations suggest that BCG facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.


Assuntos
Animais Recém-Nascidos , Vacina BCG , Glicólise , Serina-Treonina Quinases TOR , Vacinação , Animais , Camundongos , Vacina BCG/imunologia , Serina-Treonina Quinases TOR/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Transdução de Sinais , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Camundongos Endogâmicos C57BL , Humanos
14.
Immunology ; 172(1): 127-143, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38332630

RESUMO

Myeloid-derived suppressor cells (MDSCs) increase in number and gain immunosuppressive functions in tumours and many other pathological conditions. MDSCs are characterized by their strong T-cell immunosuppressive capacity. The effects that MDSCs may have on B cells, especially within the tumour microenvironment, are less well understood. Here, we report that either monocytic MDSCs or polymorphonuclear MDSCs can promote increases in interleukin (IL)-10-expressing CD19hiFcγRIIbhi regulatory B cells in vitro and in vivo. Splenic transitional-1, -2, and -3 cells and marginal zone B cells, but not follicular B cells, differentiate into IL-10-expressing CD19hiFcγRIIbhi regulatory B cells. The adoptive transfer of CD19hiFcγRIIbhi regulatory B cells via tail vein injection can promote subcutaneous 3LL tumour growth in mice. The expression of programmed death-ligand 1 on MDSCs was found to be strongly associated with CD19hiFcγRIIbhi regulatory B cell population expansion. Furthermore, the frequency of circulating CD19+FcγRIIhi regulatory B cells was significantly increased in advanced-stage lung cancer patients. Our results unveil a critical role of MDSCs in regulatory B-cell differentiation and population expansion in lung cancer patients.


Assuntos
Linfócitos B Reguladores , Neoplasias Pulmonares , Células Supressoras Mieloides , Camundongos , Humanos , Animais , Linfócitos B Reguladores/metabolismo , Células Supressoras Mieloides/metabolismo , Antígeno B7-H1/metabolismo , Diferenciação Celular , Camundongos Endogâmicos C57BL , Microambiente Tumoral
15.
Immunology ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256808

RESUMO

A disbalance between immune regulatory cells and inflammatory cells is known to drive atherosclerosis. However, the exact mechanism is not clear. Here, we investigated the homing of immune regulatory cells, mainly, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) subsets in asymptomatic coronary artery disease (CAD) risk factor-exposed young individuals (dyslipidemia [DLP] group) and stable CAD patients (CAD group). Compared with healthy controls (HCs), Tregs frequency was reduced in both DLP and CAD groups but expressed high levels of CCR5 in both groups. The frequency of monocytic-myeloid-derived suppressor cells (M-MDSCs) was increased while polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were decreased in CAD patients only. Interestingly, although unchanged in frequency, M-MDSCs of the DLP group expressed high levels of CCR5. Serum levels of chemokines (CCL5, CX3CL1, CCL26) and inflammatory cytokines (IL-6, IL-1ß, IFN-γ, TNF-α) were higher in the DLP group. Stimulation with inflammatory cytokines augmented CCR5 expression in Tregs and M-MDSCs isolated from HCs. Activated endothelial cells showed elevated levels of CX3CL1 and CCL5 in vitro. Blocking CCR5 with D-Ala-peptide T-amide (DAPTA) increased Treg and M-MDSC frequency in C57Bl6 mice fed a high-fat diet. In accelerated atherosclerosis model, DAPTA treatment led to the formation of smooth muscle-rich plaque with less macrophages. Thus, we show that CCR5-CCL5 axis is instrumental in recruiting Tregs and M-MDSCs to dysfunctional endothelium in the asymptomatic phase of atherosclerosis contributing to atherosclerosis progression. Drugs targeting CCR5 in asymptomatic and CAD risk-factor/s-exposed individuals might be a novel therapeutic regime to diminish atherogenesis.

16.
Cancer Metastasis Rev ; 42(1): 113-142, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36640224

RESUMO

The establishment of primary tumor cells in distant organs, termed metastasis, is the principal cause of cancer mortality and is a crucial therapeutic target in oncology. Thus, it is critical to establish a better understanding of metastatic progression for the future development of improved therapeutic approaches. Indeed, such development requires insight into the timing of tumor cell dissemination and seeding of distant organs resulting in occult lesions. Following dissemination of tumor cells from the primary tumor, they can reside in niches in distant organs for years or decades, following which they can emerge as an overt metastasis. This timeline of metastatic dormancy is regulated by interactions between the tumor, its microenvironment, angiogenesis, and tumor antigen-specific T-cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would help identify and aid in the development of novel targeted therapeutics. One such mediator of dormancy is myeloid derived suppressor cells (MDSC), whose number in the peripheral blood (PB) or infiltrating tumors has been associated with cancer stage, grade, patient survival, and metastasis in a broad range of tumor pathologies. Thus, extensive studies have revealed a role for MDSCs in tumor escape from adoptive and innate immune responses, facilitating tumor progression and metastasis; however, few studies have considered their role in dormancy. We have posited that MDSCs may regulate disseminated tumor cells resulting in resurgence of senescent tumor cells. In this review, we discuss clinical studies that address mechanisms of tumor recurrence including from dormancy, the role of MDSCs in their escape from dormancy during recurrence, the development of occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies. We stress that assessing the impact of therapies on MDSCs versus other cellular targets is challenging within the multimodality interventions required clinically.


Assuntos
Células Supressoras Mieloides , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Microambiente Tumoral
17.
Curr Issues Mol Biol ; 46(9): 9286-9297, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39329901

RESUMO

Myeloid-derived suppressor cells (MDSCs) are immature cells with an immunosuppressive function. MDSCs have been related to inflammation in many settings, including infections, transplantation, obesity, aging, or cancer. In oncological settings, MDSCs participate in tumor immunoescape, growth, and metastasis. Certain nutrients can modify chronic inflammation by their interaction with MDSCs. Therefore, the possible influence of certain nutrients on immune surveillance by their actions on MDSCs and how this may affect the prognosis of cancer patients were evaluated in this scoping review. We identified seven papers, six of which were murine model studies and only one was a human clinical trial. Globally, a significant reduction in cancer growth and progression was observed after achieving a reduction in both MDSCs and their immunosuppressive ability with nutrients such as selected vegetables, icaritin, retinoic acid, curdlan, active vitamin D, soy isoflavones, and green tea. In conclusion, the consumption of certain nutrients may have effects on MDSCs, with beneficial results not only in the prevention of tumor development and growth but also in improving patients' response.

18.
Clin Immunol ; 268: 110355, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39237078

RESUMO

Biliary atresia (BA) is a severe pediatric liver disease characterized by progressive bile duct destruction and fibrosis, leading to significant liver damage and frequently necessitating liver transplantation. This study elucidates the role of LOX-1+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in BA pathogenesis and assesses their potential as non-invasive early diagnostic biomarkers. Using flow cytometry, immunofluorescence, and molecular profiling, we analyzed the expression and activity of these cells in peripheral blood and liver tissues from BA patients and controls. Our findings reveal a significant increase in the frequencies and function of LOX-1+PMN-MDSCs in BA patients, along with MAPK signaling pathway upregulation, indicating their involvement in disease mechanisms. Additionally, the frequencies of LOX-1+PMN-MDSC in peripheral blood significantly positively correlate with liver function parameters in BA patients, demonstrating diagnostic performance comparable to traditional serum markers. These findings suggest that LOX-1+PMN-MDSCs contribute to the immunosuppressive environment in BA and could serve as potential diagnostic targets.

19.
Br J Haematol ; 205(3): 798-811, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39044285

RESUMO

Cells of the innate and adaptive immune systems are the progeny of haematopoietic stem and progenitor cells (HSPCs). During steady-state myelopoiesis, HSPC undergo differentiation and proliferation but are called to respond directly and acutely to various signals that lead to emergency myelopoiesis, including bone marrow ablation, infections, and sterile inflammation. There is extensive evidence that many solid tumours have the potential to secrete classical myelopoiesis-promoting growth factors and other products able to mimic emergency haematopoiesis, and to aberrantly re-direct myeloid cell development into immunosuppressive cells with tumour promoting properties. Here, we summarize the current literature regarding the effects of solid cancers on HSPCs function and discuss how these effects might shape antitumour responses via a mechanism initiated at a site distal from the tumour microenvironment.


Assuntos
Mielopoese , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Células-Tronco Hematopoéticas/patologia , Microambiente Tumoral/imunologia , Animais
20.
Eur J Immunol ; 53(12): e2250345, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37748117

RESUMO

Myeloid-derived suppressor cells (MDSCs) are well recognized as critical factors in the pathology of tumors. However, their roles in autoimmune diseases are still unclear, which hampers the development of efficient immunotherapies. The role of different MDSCs subsets in multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus displayed different mechanisms of immune suppression, and several studies pointed to MDSCs' capacity to induce T-helper (Th)17 cells and tissue damage. These results also suggested that MDSCs could be present in different functional states and utilize different mechanisms for controlling the activity of T and B cells. Therefore, various therapeutic strategies should be employed to restore homeostasis in autoimmune diseases. The therapies harnessing MDSCs could be designed either as cell therapy or rely on the expansion and activation of MDSCs in vivo, or their depletion. Cumulatively, MDSCs are inevitable players in autoimmunity, and rational approaches in developing therapies are required to avoid the adverse effects of MDSCs and harness their suppressive mechanisms to improve the overall efficacy of autoimmunity therapy.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Esclerose Múltipla , Células Supressoras Mieloides , Humanos , Autoimunidade
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