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1.
Cell ; 178(6): 1493-1508.e20, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474370

RESUMO

Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.


Assuntos
Doença de Crohn/terapia , Citocinas/imunologia , Intestinos/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Doença de Crohn/imunologia , Doença de Crohn/patologia , Humanos , Imunoterapia/métodos , Fagócitos/patologia , Análise de Célula Única , Células Estromais/patologia , Linfócitos T/patologia
2.
Nature ; 617(7960): 386-394, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37100912

RESUMO

Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.


Assuntos
Plasticidade Celular , Cobre , Inflamação , Transdução de Sinais , Animais , Camundongos , Cobre/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , NAD/metabolismo , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Peróxido de Hidrogênio/metabolismo , Epigênese Genética/efeitos dos fármacos , Metformina/análogos & derivados , Oxirredução , Plasticidade Celular/efeitos dos fármacos , Plasticidade Celular/genética , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética
3.
Nat Immunol ; 16(10): 1060-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26343536

RESUMO

Treatment with ionizing radiation (IR) can lead to the accumulation of tumor-infiltrating regulatory T cells (Treg cells) and subsequent resistance of tumors to radiotherapy. Here we focused on the contribution of the epidermal mononuclear phagocytes Langerhans cells (LCs) to this phenomenon because of their ability to resist depletion by high-dose IR. We found that LCs resisted apoptosis and rapidly repaired DNA damage after exposure to IR. In particular, we found that the cyclin-dependent kinase inhibitor CDKN1A (p21) was overexpressed in LCs and that Cdkn1a(-/-) LCs underwent apoptosis and accumulated DNA damage following IR treatment. Wild-type LCs upregulated major histocompatibility complex class II molecules, migrated to the draining lymph nodes and induced an increase in Treg cell numbers upon exposure to IR, but Cdkn1a(-/-) LCs did not. Our findings suggest a means for manipulating the resistance of LCs to IR to enhance the response of cutaneous tumors to radiotherapy.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células de Langerhans/efeitos da radiação , Radiação Ionizante , Linfócitos T Reguladores/efeitos da radiação , Animais , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Citometria de Fluxo , Camundongos , Análise em Microsséries , Reação em Cadeia da Polimerase , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Regulação para Cima
4.
Nat Immunol ; 15(1): 54-62, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24270517

RESUMO

miR-126 is a microRNA expressed predominately by endothelial cells and controls angiogenesis. We found miR-126 was required for the innate response to pathogen-associated nucleic acids and that miR-126-deficient mice had greater susceptibility to infection with pseudotyped HIV. Profiling of miRNA indicated that miR-126 had high and specific expression by plasmacytoid dendritic cells (pDCs). Moreover, miR-126 controlled the survival and function of pDCs and regulated the expression of genes encoding molecules involved in the innate response, including Tlr7, Tlr9 and Nfkb1, as well as Kdr, which encodes the growth factor receptor VEGFR2. Deletion of Kdr in DCs resulted in reduced production of type I interferon, which supports the proposal of a role for VEGFR2 in miR-126 regulation of pDCs. Our studies identify the miR-126-VEGFR2 axis as an important regulator of the innate response that operates through multiscale control of pDCs.


Assuntos
Células Dendríticas/imunologia , Imunidade Inata/imunologia , MicroRNAs/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Animais , Células Dendríticas/metabolismo , Citometria de Fluxo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Imunidade Inata/genética , Immunoblotting , Interferon-alfa/sangue , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/imunologia , Subunidade p50 de NF-kappa B/metabolismo , Ácidos Nucleicos/imunologia , Ácidos Nucleicos/metabolismo , Oligodesoxirribonucleotídeos/genética , Oligodesoxirribonucleotídeos/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo , Transcriptoma/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Immunity ; 44(4): 924-38, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-27096321

RESUMO

Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.


Assuntos
Antígenos CD/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Cadeias alfa de Integrinas/metabolismo , Melanoma Experimental/imunologia , Poli I-C/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/farmacologia , Animais , Apresentação de Antígeno/imunologia , Linhagem Celular Tumoral , Células Dendríticas/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout
6.
J Neurosci ; 35(12): 4837-50, 2015 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-25810515

RESUMO

Multiple sclerosis (MS) is an inflammatory disease of the CNS thought to be driven by CNS-specific T lymphocytes. Although CD8(+) T cells are frequently found in multiple sclerosis lesions, their distinct role remains controversial because direct signs of cytotoxicity have not been confirmed in vivo. In the present work, we determined that murine ovalbumin-transgenic (OT-1) CD8(+) T cells recognize the myelin peptide myelin oligodendrocyte glycoprotein 40-54 (MOG40-54) both in vitro and in vivo. The aim of this study was to investigate whether such cross-recognizing CD8(+) T cells are capable of inducing CNS damage in vivo. Using intravital two-photon microscopy in the mouse model of multiple sclerosis, we detected antigen recognition motility of the OT-1 CD8(+) T cells within the CNS leading to a selective enrichment in inflammatory lesions. However, this cross-reactivity of OT-1 CD8(+) T cells with MOG peptide in the CNS did not result in clinically or subclinically significant damage, which is different from myelin-specific CD4(+) Th17-mediated autoimmune pathology. Therefore, intravital imaging demonstrates that local myelin recognition by autoreactive CD8(+) T cells in inflammatory CNS lesions alone is not sufficient to induce disability or increase axonal injury.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/patologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Degeneração Neural/imunologia , Animais , Autoimunidade/imunologia , Morte Celular , Proliferação de Células , Células Cultivadas , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/imunologia
8.
Cell Mol Life Sci ; 70(23): 4431-48, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23649148

RESUMO

The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells.


Assuntos
Matriz Extracelular/imunologia , Vigilância Imunológica/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Movimento Celular/imunologia , Progressão da Doença , Matriz Extracelular/metabolismo , Humanos , Modelos Imunológicos , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Linfócitos T/citologia , Linfócitos T/metabolismo
9.
Sci Immunol ; 8(79): eabn6612, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36638189

RESUMO

T cells that recognize tumor antigens are crucial for mounting antitumor immune responses. Induction of antitumor T cells in immunogenic tumors depends on STING, the intracellular innate immune receptor for cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and related cyclic dinucleotides (CDNs). However, the optimal way to leverage STING activation in nonimmunogenic tumors is still unclear. Here, we show that cGAMP delivery by intratumoral injection of virus-like particles (cGAMP-VLP) led to differentiation of circulating tumor-specific T cells, decreased tumor regulatory T cells (Tregs), and antitumoral responses that synergized with PD1 blockade. By contrast, intratumoral injection of the synthetic CDN ADU-S100 led to tumor necrosis and systemic T cell activation but simultaneously depleted immune cells from injected tumors and induced minimal priming of circulating tumor-specific T cells. The antitumor effects of cGAMP-VLP required type 1 conventional dendritic cells (cDC1), whereas ADU-S100 eliminated cDC1 from injected tumors. cGAMP-VLP preferentially targeted STING in dendritic cells at a 1000-fold smaller dose than ADU-S100. Subcutaneous administration of cGAMP-VLP showed synergy when combined with PD1 blockade or a tumor Treg-depleting antibody to elicit systemic tumor-specific T cells and antitumor activity, leading to complete and durable tumor eradication in the case of tumor Treg depletion. These findings show that cell targeting of STING stimulation shapes the antitumor T cell response and identify a therapeutic strategy to enhance T cell-targeted immunotherapy.


Assuntos
Neoplasias , Linfócitos T , Humanos , Imunidade , Células Dendríticas
10.
Nat Cell Biol ; 25(9): 1332-1345, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37605008

RESUMO

MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic T cells, characteristics consistent with a compromised anti-tumour response. Single cell and spatial transcriptomics identify increased dedifferentiation along the neural crest lineage of the tumour compartment and increased frequency and activation of cancer-associated fibroblasts following macroH2A loss. Mechanistically, macroH2A-deficient cancer-associated fibroblasts display increased myeloid chemoattractant activity as a consequence of hyperinducible expression of inflammatory genes, which is enforced by increased chromatin looping of their promoters to enhancers that gain H3K27ac. In summary, we reveal a tumour suppressive role for macroH2A variants through the regulation of chromatin architecture in the tumour stroma with potential implications for human melanoma.


Assuntos
Fibroblastos Associados a Câncer , Histonas , Melanoma , Animais , Camundongos , Cromatina/genética , Expressão Gênica , Histonas/genética , Melanoma/genética , Microambiente Tumoral/genética
11.
Cancer Discov ; 12(11): 2606-2625, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36027053

RESUMO

It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell-permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (FAP+αSMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T-cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCE: The cellular and molecular programs driving T-cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T-cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to developing new strategies targeting T cell-excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Pulmonares , Humanos , Fibroblastos Associados a Câncer/patologia , Linfócitos T , Microambiente Tumoral , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Fibroblastos
12.
Cancer Cell ; 39(12): 1594-1609.e12, 2021 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-34767762

RESUMO

Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1+CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). We confirmed LCAMhi enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAMhi lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Análise de Célula Única/métodos , Humanos
13.
Nat Rev Cancer ; 19(4): 215-227, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30867580

RESUMO

Although common evolutionary principles drive the growth of cancer cells regardless of the tissue of origin, the microenvironment in which tumours arise substantially differs across various organ sites. Recent studies have established that, in addition to cell-intrinsic effects, tumour growth regulation also depends on local cues driven by tissue environmental factors. In this Review, we discuss how tissue-specific determinants might influence tumour development and argue that unravelling the tissue-specific contribution to tumour immunity should help the development of precise immunotherapeutic strategies for patients with cancer.


Assuntos
Neoplasias/imunologia , Animais , Proliferação de Células/fisiologia , Humanos , Neoplasias/patologia , Microambiente Tumoral/imunologia
15.
Cell Rep ; 23(12): 3658-3672.e6, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29925006

RESUMO

The IRF8-dependent subset of classical dendritic cells (cDCs), termed cDC1, is important for cross-priming cytotoxic T cell responses against pathogens and tumors. Culture of hematopoietic progenitors with DC growth factor FLT3 ligand (FLT3L) yields very few cDC1s (in humans) or only immature "cDC1-like" cells (in the mouse). We report that OP9 stromal cells expressing the Notch ligand Delta-like 1 (OP9-DL1) optimize FLT3L-driven development of cDC1s from murine immortalized progenitors and primary bone marrow cells. Co-culture with OP9-DL1 induced IRF8-dependent cDC1s with a phenotype (CD103+ Dec205+ CD8α+) and expression profile resembling primary splenic cDC1s. OP9-DL1-induced cDC1s showed preferential migration toward CCR7 ligands in vitro and superior T cell cross-priming and antitumor vaccination in vivo. Co-culture with OP9-DL1 also greatly increased the yield of IRF8-dependent CD141+ cDC1s from human bone marrow progenitors cultured with FLT3L. Thus, Notch signaling optimizes cDC generation in vitro and yields authentic cDC1s for functional studies and translational applications.


Assuntos
Apresentação Cruzada , Células Dendríticas/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Células da Medula Óssea/citologia , Diferenciação Celular , Movimento Celular , Células Dendríticas/citologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Receptores CCR7/metabolismo , Vacinação
16.
Nat Commun ; 9(1): 3503, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158554

RESUMO

Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Animais , Transição Epitelial-Mesenquimal/genética , Expressão Gênica/genética , Predisposição Genética para Doença , Humanos , Camundongos , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Exp Med ; 215(1): 319-336, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29263218

RESUMO

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal-related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)-mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.


Assuntos
Movimento Celular/fisiologia , Células Dendríticas/metabolismo , Células Dendríticas/fisiologia , Histiocitose de Células de Langerhans/metabolismo , Células de Langerhans/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Animais , Apoptose/fisiologia , Histiocitose de Células de Langerhans/patologia , Humanos , Células de Langerhans/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação/fisiologia , Fagocitose/fisiologia
19.
J Exp Med ; 211(4): 669-83, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24638167

RESUMO

Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.


Assuntos
Diferenciação Celular , Células Dendríticas/metabolismo , Predisposição Genética para Doença , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Antígenos CD34/metabolismo , Antígenos de Superfície/metabolismo , Medula Óssea/patologia , Antígeno CD11c/metabolismo , Linhagem da Célula , Criança , Pré-Escolar , Feminino , Células-Tronco Hematopoéticas/metabolismo , Histiocitose de Células de Langerhans/sangue , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Lactente , Lectinas Tipo C/metabolismo , Masculino , Lectinas de Ligação a Manose/metabolismo , Camundongos , Fenótipo , Fatores de Risco , Resultado do Tratamento
20.
Oncoimmunology ; 1(6): 992-994, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23162783

RESUMO

In principle, T cells can recognize and kill cancer cells. However, tumors have the ability to escape T cell attack. By imaging the dynamic behavior of T cells in human lung tumor explants, we have recently established the importance of the extracellular matrix in limiting access of T cells to tumor cells.

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