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1.
Cell ; 185(23): 4317-4332.e15, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36302380

RESUMO

Therapeutic cancer vaccines are designed to increase tumor-specific T cell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit T cell function. Here, we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8+ T cells that infiltrated tumors. However, only SNP-IV mediated tumor regression, dependent on systemic type I interferon at the time of boost. Single-cell RNA-sequencing revealed that intratumoral monocytes expressing an immunoregulatory gene signature (Chil3, Anxa2, Wfdc17) were reduced after SNP-IV boost. In humans, the Chil3+ monocyte gene signature is enriched in CD16- monocytes and associated with worse outcomes. Our results show that the generation of tumor-specific CD8+ T cells combined with remodeling of the TME is a promising approach for tumor immunotherapy.


Assuntos
Vacinas Anticâncer , Microambiente Tumoral , Humanos , Camundongos , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Imunoterapia/métodos , Antígenos de Neoplasias , Vacinação/métodos , Adjuvantes Imunológicos
2.
Cell ; 184(13): 3394-3409.e20, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34077752

RESUMO

The human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth.


Assuntos
Bactérias/metabolismo , Desenvolvimento Embrionário , Feto/citologia , Feto/microbiologia , Leucócitos/citologia , Adulto , Bactérias/genética , Bactérias/ultraestrutura , Proliferação de Células , Células Dendríticas/metabolismo , Feminino , Feto/ultraestrutura , Trato Gastrointestinal/embriologia , Trato Gastrointestinal/ultraestrutura , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Viabilidade Microbiana , Gravidez , Segundo Trimestre da Gravidez , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Reprodutibilidade dos Testes , Linfócitos T/citologia
3.
Cell ; 183(2): 377-394.e21, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32976798

RESUMO

We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of ∼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.


Assuntos
Carcinoma Hepatocelular/patologia , Células Endoteliais/metabolismo , Microambiente Tumoral/genética , Adulto , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Receptor 2 de Folato/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Fígado/patologia , Neoplasias Hepáticas/genética , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/genética , Transcriptoma/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Immunity ; 54(8): 1883-1900.e5, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34331874

RESUMO

Mononuclear phagocytes (MNPs) encompass dendritic cells, monocytes, and macrophages (MoMac), which exhibit antimicrobial, homeostatic, and immunoregulatory functions. We integrated 178,651 MNPs from 13 tissues across 41 datasets to generate a MNP single-cell RNA compendium (MNP-VERSE), a publicly available tool to map MNPs and define conserved gene signatures of MNP populations. Next, we generated a MoMac-focused compendium that revealed an array of specialized cell subsets widely distributed across multiple tissues. Specific pathological forms were expanded in cancer and inflammation. All neoplastic tissues contained conserved tumor-associated macrophage populations. In particular, we focused on IL4I1+CD274(PD-L1)+IDO1+ macrophages, which accumulated in the tumor periphery in a T cell-dependent manner via interferon-γ (IFN-γ) and CD40/CD40L-induced maturation from IFN-primed monocytes. IL4I1_Macs exhibited immunosuppressive characteristics through tryptophan degradation and promoted the entry of regulatory T cell into tumors. This integrated analysis provides a robust online-available platform for uniform annotation and dissection of specific macrophage functions in healthy and pathological states.


Assuntos
Células Dendríticas/imunologia , Expressão Gênica/imunologia , Monócitos/imunologia , Transcriptoma/genética , Macrófagos Associados a Tumor/imunologia , Artrite Reumatoide/imunologia , COVID-19/imunologia , Expressão Gênica/genética , Perfilação da Expressão Gênica , Humanos , Interferon gama/imunologia , L-Aminoácido Oxidase/metabolismo , Cirrose Hepática/imunologia , Macrófagos/imunologia , Neoplasias/imunologia , RNA Citoplasmático Pequeno/genética , Análise de Célula Única , Linfócitos T Reguladores/imunologia , Transcriptoma/imunologia
5.
Nature ; 623(7986): 397-405, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37914940

RESUMO

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain1. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues2-6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7-10. However, current approaches do not incorporate microglia or address their role in organoid maturation11-21. Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac)22. In organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogenesis.


Assuntos
Encéfalo , Colesterol , Células-Tronco Pluripotentes Induzidas , Microglia , Células-Tronco Neurais , Neurogênese , Organoides , Animais , Humanos , Camundongos , Encéfalo/citologia , Encéfalo/metabolismo , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Microglia/citologia , Microglia/metabolismo , Organoides/citologia , Organoides/metabolismo , Colesterol/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Axônios , Proliferação de Células , Ésteres/metabolismo , Gotículas Lipídicas/metabolismo
6.
Immunity ; 51(3): 573-589.e8, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31474513

RESUMO

Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5-CD163+CD14+ cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies.


Assuntos
Biomarcadores/sangue , Células Dendríticas/imunologia , Inflamação/sangue , Inflamação/imunologia , Leucócitos Mononucleares/imunologia , Fagócitos/imunologia , Antígenos CD/sangue , Antígenos CD/imunologia , Células Cultivadas , Citometria de Fluxo/métodos , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/imunologia , Fenótipo , Análise de Célula Única
7.
Cell Rep ; 42(6): 112599, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37279110

RESUMO

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 T cell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 T cells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.


Assuntos
Linfócitos T CD8-Positivos , Vacinação , Humanos , Camundongos , Animais , Imunidade Adaptativa , Vetores Genéticos , Adjuvantes Imunológicos
8.
Sci Immunol ; 7(78): eadd3330, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36525505

RESUMO

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.


Assuntos
Histiocitose de Células de Langerhans , Neoplasias , Humanos , Linhagem da Célula , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Diferenciação Celular , Monócitos/metabolismo
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