Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
EMBO Mol Med ; 13(1): e12850, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33372722

RESUMO

Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.

2.
Cell Rep ; 33(13): 108571, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33378668

RESUMO

Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPß. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.

3.
Gynecol Oncol Rep ; 34: 100655, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33083509

RESUMO

Agonists of the co-stimulatory molecule OX40 (CD134) are in clinical assessment alone and in combination with other immunotherapies. Recent pre-clinical studies have suggested that concurrent administration of OX40 agonists with anti-PD1 therapy is detrimental to the efficacy of such combinations and maximal efficacy may require sequential administration of the OX40 agonist followed by anti-PD1 therapy. In this report, we detail two patients with advanced ovarian carcinoma were treated with INCAGN01949, an agonistic OX40 Ab, as part of a clinical trial until disease progression. Both patients then received the combination of ipilimumab and nivolumab and experienced unusually deep and durable responses. These cases support the hypothesis raised in pre-clinical studies and highlight the potential relevance of sequence in combinational immunotherapy.

4.
Dev Biol ; 456(2): 212-225, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31509769

RESUMO

The tentacular system of Clytia hemisphaerica medusa (Cnidaria, Hydrozoa) has recently emerged as a promising experimental model to tackle the developmental mechanisms that regulate cell lineage progression in an early-diverging animal phylum. From a population of proximal stem cells, the successive steps of tentacle stinging cell (nematocyte) elaboration, are spatially ordered along a "cellular conveyor belt". Furthermore, the C. hemisphaerica tentacular system exhibits bilateral organisation, with two perpendicular polarity axes (proximo-distal and oral-aboral). We aimed to improve our knowledge of this cellular system by combining RNAseq-based differential gene expression analyses and expression studies of Wnt signalling genes. RNAseq comparisons of gene expression levels were performed (i) between the tentacular system and a control medusa deprived of all tentacles, nematogenic sites and gonads, and (ii) between three samples staggered along the cellular conveyor belt. The behaviour in these differential expression analyses of two reference gene sets (stem cell genes; nematocyte genes), as well as the relative representations of selected gene ontology categories, support the validity of the cellular conveyor belt model. Expression patterns obtained by in situ hybridisation for selected highly differentially expressed genes and for Wnt signalling genes are largely consistent with the results from RNAseq. Wnt signalling genes exhibit complex spatial deployment along both polarity axes of the tentacular system, with the Wnt/ß-catenin pathway probably acting along the oral-aboral axis rather than the proximo-distal axis. These findings reinforce the idea that, despite overall radial symmetry, cnidarians have a full potential for elaboration of bilateral structures based on finely orchestrated deployment of an ancient developmental gene toolkit.


Assuntos
Padronização Corporal/genética , Hidrozoários/genética , Via de Sinalização Wnt/genética , Animais , Biologia do Desenvolvimento/métodos , Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Hidrozoários/metabolismo
5.
J Exp Med ; 216(9): 2150-2169, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31239386

RESUMO

We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be controlled by the down-regulation of Rb1, but not IRF8, which is known to regulate the expansion of PMN-MDSCs from classic granulocyte precursors. In cancer patients, putative MLPGs were found within the population of CXCR1+CD15-CD14+HLA-DR-/lo monocytic cells. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSCs.


Assuntos
Monócitos/patologia , Células Supressoras Mieloides/patologia , Neoplasias/patologia , Neutrófilos/patologia , Adulto , Idoso , Animais , Diferenciação Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas de Ligação a Retinoblastoma/metabolismo
6.
Nat Ecol Evol ; 3(5): 801-810, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30858591

RESUMO

Jellyfish (medusae) are a distinctive life-cycle stage of medusozoan cnidarians. They are major marine predators, with integrated neurosensory, muscular and organ systems. The genetic foundations of this complex form are largely unknown. We report the draft genome of the hydrozoan jellyfish Clytia hemisphaerica and use multiple transcriptomes to determine gene use across life-cycle stages. Medusa, planula larva and polyp are each characterized by distinct transcriptome signatures reflecting abrupt life-cycle transitions and all deploy a mixture of phylogenetically old and new genes. Medusa-specific transcription factors, including many with bilaterian orthologues, associate with diverse neurosensory structures. Compared to Clytia, the polyp-only hydrozoan Hydra has lost many of the medusa-expressed transcription factors, despite similar overall rates of gene content evolution and sequence evolution. Absence of expression and gene loss among Clytia orthologues of genes patterning the anthozoan aboral pole, secondary axis and endomesoderm support simplification of planulae and polyps in Hydrozoa, including loss of bilateral symmetry. Consequently, although the polyp and planula are generally considered the ancestral cnidarian forms, in Clytia the medusa maximally deploys the ancestral cnidarian-bilaterian transcription factor gene complement.


Assuntos
Hidrozoários , Animais , Evolução Molecular , Genoma
7.
Cancer Cell ; 32(5): 654-668.e5, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29136508

RESUMO

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Monócitos/metabolismo , Células Supressoras Mieloides/metabolismo , Neoplasias Experimentais/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Granulócitos/metabolismo , Histona Desacetilase 2 , Humanos , Imidazóis/farmacologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Carga Tumoral/efeitos dos fármacos
8.
Clin Cancer Res ; 23(12): 2942-2950, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27965309

RESUMO

Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs.Experimental Design: The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated.Results: The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies.Conclusions: Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942-50. ©2016 AACR.


Assuntos
Imunoterapia , Células Supressoras Mieloides/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Intervalo Livre de Doença , Humanos , Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Monócitos/imunologia , Células Mieloides/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas
9.
Immunity ; 44(2): 303-15, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26885857

RESUMO

Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy.


Assuntos
Hipóxia/imunologia , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/imunologia , Monoéster Fosfórico Hidrolases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Dimerização , Feminino , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Monoéster Fosfórico Hidrolases/genética , Fator de Transcrição STAT3/genética , Ácidos Siálicos/metabolismo , Microambiente Tumoral
10.
Sci Immunol ; 1(2)2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28417112

RESUMO

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5-15% of total neutrophils in cancer patients and 15-50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1- counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.

11.
Cancer Lett ; 371(1): 117-24, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26639197

RESUMO

Multiple myeloma (MM) is an incurable cancer of plasma cells localized preferentially in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in MM management. BM microenvironment is known to play a critical role in protection of MM cells from chemotherapeutics; however, mechanisms responsible for this effect are largely unknown. Development of MM is associated with accumulation of myeloid-derived suppressor cells (MDSCs) mostly represented by pathologically activated relatively immature polymorphonuclear neutrophils (PMN-MDSCs). Here, we investigated whether PMN-MDSCs are responsible for BM microenvironment-mediated MM chemoresistance. Using in vivo mouse models allowing manipulation of myeloid cell number, we demonstrated a critical role for myeloid cells in MM growth and chemoresistance. PMN-MDSCs isolated from MM-bearing host are immunosuppressive and thus, functionally distinct from their counterpart in tumor-free host neutrophils. We found, however, that both PMN-MDSCs and neutrophils equally promote MM survival from doxorubicin and melphalan and that this effect is mediated by soluble factors rather than direct cell-cell contact. Our data indicate that targeting PMN-MDSCs would enhance chemotherapy efficacy in MM.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Melfalan/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Linhagem da Célula , Técnicas de Cocultura , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Comunicação Parácrina , Fenótipo , Fatores de Tempo , Células Tumorais Cultivadas , Microambiente Tumoral
12.
J Leukoc Biol ; 98(6): 913-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26337512

RESUMO

Myeloid-derived suppressor cells are a heterogeneous group of pathologically activated immature cells that play a major role in the negative regulation of the immune response in cancer, autoimmunity, many chronic infections, and inflammatory conditions, as well as in the regulation of tumor angiogenesis, tumor cell invasion, and metastases. Accumulation of myeloid-derived suppressor cells is governed by a network of transcriptional regulators that could be combined into 2 partially overlapping groups: factors promoting myelopoiesis and preventing differentiation of mature myeloid cells and factors promoting pathologic activation of myeloid-derived suppressor cells. In this review, we discuss the specific nature of these factors and their impact on myeloid-derived suppressor cell development.


Assuntos
Células Mieloides/imunologia , Mielopoese/imunologia , Neoplasias/imunologia , Neovascularização Patológica/imunologia , Fatores de Transcrição/imunologia , Transcrição Genética/imunologia , Animais , Humanos , Células Mieloides/patologia , Invasividade Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/patologia
13.
J Exp Med ; 212(3): 351-67, 2015 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-25667306

RESUMO

Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33+S100A9+ cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17-producing CD4+ T cells. This chemokine was released by activated IMCs. Elimination of CD4+ T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4+ T cells.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Células Mieloides/patologia , Neoplasias Cutâneas/patologia , Animais , Linfócitos T CD4-Positivos/imunologia , Calgranulina B/metabolismo , Transformação Celular Neoplásica/patologia , Quimiocina CCL4/metabolismo , Colite/metabolismo , Colite/patologia , Feminino , Humanos , Camundongos Transgênicos , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/toxicidade
14.
Annu Rev Med ; 66: 97-110, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25341012

RESUMO

Accumulation of pathologically activated immature myeloid cells with potent immune-suppressive activity is one of the major immunological hallmarks of cancer. In recent years, it became clear that in addition to their immune-suppressive activity, myeloid-derived suppressor cells (MDSCs) influence tumor progression in a variety of ways. They are directly implicated in the promotion of tumor metastases by participating in the formation of premetastatic niches, promoting angiogenesis and tumor cell invasion. In this review, we discuss recent data describing various roles of MDSCs in the formation of tumor metastases.


Assuntos
Células Mieloides/imunologia , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Humanos , Invasividade Neoplásica/imunologia , Neovascularização Patológica/imunologia
15.
Immunity ; 41(3): 341-342, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25238087

RESUMO

Myeloid-derived suppressor cells (MDSCs) are one of the major negative regulators of immune responses. In this issue of Immunity, Thevenot et al. (2014) showed that in tumors, the suppressive activity of MDSCs is regulated by transcription factor Chop.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/imunologia , Linfócitos T/imunologia , Fator de Transcrição CHOP/genética , Evasão Tumoral/imunologia , Animais , Feminino
16.
J Clin Invest ; 124(6): 2626-39, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24789911

RESUMO

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.


Assuntos
Estresse do Retículo Endoplasmático , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Apoptose/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Biológicos , Células Mieloides/patologia
17.
J Immunol ; 192(6): 2920-31, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24554775

RESUMO

Cross-presentation is one of the main features of dendritic cells (DCs), which is critically important for the development of spontaneous and therapy-inducible antitumor immune responses. Patients, at early stages of cancer, have normal presence of DCs. However, the difficulties in the development of antitumor responses in patients with low tumor burden raised the question of the mechanisms of DC dysfunction. In this study, we found that, in differentiated DCs, tumor-derived factors blocked the cross-presentation of exogenous Ags without inhibiting the Ag presentation of endogenous protein or peptides. This effect was caused by intracellular accumulation of different types of oxidized neutral lipids: triglycerides, cholesterol esters, and fatty acids. In contrast, the accumulation of nonoxidized lipids did not affect cross-presentation. Oxidized lipids blocked cross-presentation by reducing the expression of peptide-MHC class I complexes on the cell surface. Thus, this study suggests the novel role of oxidized lipids in the regulation of cross-presentation.


Assuntos
Apresentação do Antígeno/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Lipídeos/imunologia , Neoplasias/imunologia , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Interferon gama/farmacologia , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neoplasias/metabolismo , Neoplasias/patologia , Ovalbumina/imunologia , Oxirredução , Fragmentos de Peptídeos/imunologia
18.
J Immunol ; 190(7): 3815-23, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23460744

RESUMO

Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the immune response in cancer. However, their role in bone marrow (BM), the site of primary localization of multiple myeloma (MM), is poorly understood. In this study, we found a significant accumulation of CD11b(+)CD14(-)CD33(+) immunosuppressive MDSC in BM of patients with newly diagnosed MM. To assess the possible role of MDSC in MM, we used immunocompetent mouse models. Immunosuppressive MDSC accumulated in BM of mice as early as 1 wk after tumor inoculation. S100A9 knockout (KO) mice, which are deficient in their ability to accumulate MDSC in tumor-bearing hosts, demonstrated reduced MDSC accumulation in BM after injection of MM cells compared with wild-type mice. Growth of the immunogenic MM cells was significantly reduced in S100A9KO mice. This effect was associated with the accumulation of Ag-specific CD8(+) T cells in BM and spleens of S100A9KO mice, but not wild-type mice, and was abrogated by the administration of anti-CD8 Ab or adoptive transfer of MDSC. Thus, the accumulation of MDSC at early stages of MM plays a critical role in MM progression and suggests that MDSC can be considered a possible therapeutic target in this disease.


Assuntos
Medula Óssea/imunologia , Medula Óssea/patologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Células Mieloides/imunologia , Linfócitos T/imunologia , Animais , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Camundongos , Camundongos Knockout , Mieloma Múltiplo/mortalidade , Células Mieloides/metabolismo , Fenótipo , Transplante Isogênico
19.
Nat Immunol ; 14(3): 211-20, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23354483

RESUMO

Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C(hi)Ly6G(-) inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.


Assuntos
Inativação Gênica , Genes do Retinoblastoma , Células Mieloides/patologia , Neoplasias/genética , Animais , Diferenciação Celular , Células Dendríticas/imunologia , Epigênese Genética , Macrófagos/imunologia , Camundongos , Monócitos/imunologia , Células Mieloides/metabolismo , Neoplasias/patologia , Fenótipo , Proteína do Retinoblastoma/genética
20.
Trends Immunol ; 32(1): 19-25, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21067974

RESUMO

Myeloid-derived suppressor cells (MDSCs) are one of the main cell populations responsible for regulating immune responses. MDSCs accumulate during tumor progression, autoimmunity, chronic infection and other pathological conditions, and can potently suppress T cell function. Recent studies have demonstrated the ability of MDSCs to modulate the activity of NK and myeloid cells and have implicated MDSCs in the induction of regulatory T cells. Here, we discuss recent findings that describe the molecular mechanisms that regulate the expansion and function of MDSCs, as well as recent attempts to use MDSCs in cell therapy for different pathologic conditions.


Assuntos
Células Mieloides/citologia , Células Mieloides/imunologia , Animais , Diferenciação Celular , Humanos , Tolerância Imunológica , Linfócitos/imunologia , Linfócitos T/imunologia , Fatores de Transcrição/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...