Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 63
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Nature ; 618(7967): 1033-1040, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37316667

RESUMO

Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7-10. Here, we describe a mechanism whereby a small number of CD4+ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+ T cell targeting. The CD4+ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that T helper type 1 cell-directed CD4+ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+ T cells and natural killer cells and advance cancer immunotherapies.


Assuntos
Linfócitos T CD4-Positivos , Morte Celular , Imunoterapia , Inflamação , Neoplasias , Microambiente Tumoral , Humanos , Células Apresentadoras de Antígenos/imunologia , Antígeno CD11c/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Morte Celular/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Imunidade Inata , Inflamação/imunologia , Interferons/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Células Mieloides/imunologia , Células Th1/citologia , Células Th1/imunologia
2.
Immunity ; 47(4): 789-802.e9, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29045907

RESUMO

Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.


Assuntos
Imunoterapia/métodos , Neoplasias Experimentais/terapia , Neutrófilos/imunologia , Proteínas Proto-Oncogênicas c-met/imunologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
3.
Int J Cancer ; 150(1): 142-151, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34528710

RESUMO

Most melanoma-associated deaths result from the early development of metastasis. Toll-like receptor 4 (TLR4) expression on nontumor cells is well known to contribute to tumor development and metastatic progression. The role of TLR4 expression on tumor cells however is less well understood. Here we describe TLR4 as a driver of tumor progression and metastatic spread of melanoma cells by employing a transplantable mouse melanoma model. HCmel12 melanoma cells lacking functional TLR4 showed increased sensitivity to tumor necrosis factor α induced cell killing in vitro compared to cells with intact TLR4. Interestingly, TLR4 knockout melanoma cells also showed impaired migratory capacity in vitro and a significantly reduced ability to metastasize to the lungs after subcutaneous transplantation in vivo. Finally, we demonstrate that activation of TLR4 also promotes migration in a subset of human melanoma cell lines. Our work describes TLR4 as an important mediator of melanoma migration and metastasis and provides a rationale for therapeutic inhibition of TLR4 in melanoma.


Assuntos
Movimento Celular , Neoplasias Pulmonares/secundário , Melanoma/patologia , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Sistemas CRISPR-Cas , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Células Tumorais Cultivadas
4.
Int J Mol Sci ; 23(13)2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35806489

RESUMO

Inflammatory diseases of the skin, including atopic dermatitis and psoriasis, have gained increasing attention with rising incidences in developed countries over the past decades. While bodily properties, such as immunological responses of the skin, have been described in some detail, interactions with the brain via different routes are less well studied. The suggested routes of the skin-brain axis comprise the immune system, HPA axis, and the peripheral and central nervous system, including microglia responses and structural changes. They provide starting points to investigate the molecular mechanisms of neuropsychiatric comorbidities in AD and psoriasis. To this end, mouse models exist for AD and psoriasis that could be tested for relevant behavioral entities. In this review, we provide an overview of the current mouse models and assays. By combining an extensive behavioral characterization and state-of-the-art genetic interventions with the investigation of underlying molecular pathways, insights into the mechanisms of the skin-brain axis in inflammatory cutaneous diseases are examined, which will spark further research in humans and drive the development of novel therapeutic strategies.


Assuntos
Dermatite Atópica , Psoríase , Animais , Dermatite Atópica/tratamento farmacológico , Modelos Animais de Doenças , Sistema Hipotálamo-Hipofisário , Camundongos , Sistema Hipófise-Suprarrenal , Psoríase/tratamento farmacológico , Pele
6.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925601

RESUMO

Mast cells (MCs) are best-known as key effector cells of immediate-type allergic reactions that may even culminate in life-threatening anaphylactic shock syndromes. However, strategically positioned at the host-environment interfaces and equipped with a plethora of receptors, MCs also play an important role in the first-line defense against pathogens. Their main characteristic, the huge amount of preformed proinflammatory mediators embedded in secretory granules, allows for a rapid response and initiation of further immune effector cell recruitment. The same mechanism, however, may account for detrimental overshooting responses. MCs are not only detrimental in MC-driven diseases but also responsible for disease exacerbation in other inflammatory disorders. Focusing on the skin as the largest immune organ, we herein review both beneficial and detrimental functions of skin MCs, from skin barrier integrity via host defense mechanisms to MC-driven inflammatory skin disorders. Moreover, we emphasize the importance of IgE-independent pathways of MC activation and their role in sustained chronic skin inflammation and disease exacerbation.


Assuntos
Mastócitos/imunologia , Mastócitos/metabolismo , Pele/imunologia , Anafilaxia/imunologia , Animais , Dermatite/imunologia , Humanos , Inflamação/imunologia , Vesículas Secretórias/imunologia , Vesículas Secretórias/metabolismo , Pele/metabolismo
7.
Int J Cancer ; 147(10): 2902-2913, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32790916

RESUMO

The aryl hydrocarbon receptor (AHR) is a ligand binding-transcription factor of the basic helix-loop-helix family regulating multiple cellular functions such as differentiation, cell cycle, apoptosis, and inflammatory reactions. In neoplastic diseases, the AHR has been described to modulate proliferation and differentiation in dichotomous ways, either inhibiting or augmenting the growth of tumors. The precise role of AHR in melanoma is mostly unknown. Here, we report a functional effect of AHR activation on inflammation-induced melanoma cell dedifferentiation and the development of lung metastases in a mouse model. Via in silico analyses of "The Cancer Genome Atlas" human melanoma cohort, we detected a correlation between AHR expression levels and a dedifferentiated melanoma cell phenotype with an invasive gene signature, which we were able to functionally recapitulate in a panel of human melanoma cell lines. Both human and mouse melanoma cell lines upregulated AHR expression after inflammatory stimulation with tumor necrosis factor-α (TNF-α). Activation of AHR in human and mouse melanoma cell lines with the endogenous ligand formylindolo(3,2-b)carbazole (FICZ) promoted inflammation-induced dedifferentiation in vitro. Importantly, mouse melanoma cells with CRISPR/Cas9-mediated disruption of the AHR gene showed impaired in vivo tumor growth after transplantation in the skin as well as decreased numbers of spontaneous lung metastases. Taken together, our results demonstrate a functional role for AHR expression in melanoma development and metastatic progression. This provides a scientific basis for future experiments that further dissect the underlying molecular mechanisms and assess the potential for AHR inhibition as part of multimodal melanoma treatment strategies.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Melanoma/patologia , Receptores de Hidrocarboneto Arílico/genética , Fator de Necrose Tumoral alfa/farmacologia , Animais , Carbazóis/farmacologia , Desdiferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Melanoma/genética , Camundongos , Transplante de Neoplasias , Regulação para Cima
8.
Nature ; 507(7490): 109-13, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24572365

RESUMO

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.


Assuntos
Inflamação/etiologia , Neoplasias Pulmonares/secundário , Melanoma/irrigação sanguínea , Melanoma/patologia , Neoplasias Cutâneas/patologia , Queimadura Solar/etiologia , Raios Ultravioleta , Animais , Movimento Celular/efeitos da radiação , Transformação Celular Neoplásica/efeitos da radiação , Modelos Animais de Doenças , Progressão da Doença , Feminino , Proteína HMGB1/metabolismo , Imunidade Inata/efeitos da radiação , Queratinócitos/metabolismo , Queratinócitos/patologia , Queratinócitos/efeitos da radiação , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/etiologia , Masculino , Melanócitos/patologia , Melanócitos/efeitos da radiação , Melanoma/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/etiologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/etiologia , Queimadura Solar/complicações , Receptor 4 Toll-Like/metabolismo
9.
Int J Mol Sci ; 21(2)2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940843

RESUMO

Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2-/- and Cnr1-/-/Cnr2-/- bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1-/- DCs. In vitro stimulated Cnr2-/- DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2-/- DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2-/- DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.


Assuntos
Células Dendríticas/imunologia , Dermatite Alérgica de Contato/imunologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Quimiotaxia , Células Dendríticas/citologia , Dermatite Alérgica de Contato/genética , Dinitrofluorbenzeno/toxicidade , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptores CCR4/genética , Receptores CCR4/metabolismo , Receptores CCR7/genética , Receptores CCR7/metabolismo
10.
J Dtsch Dermatol Ges ; 18(11): 1245-1248, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32954611

RESUMO

Uveal melanoma is the most common form of eye cancer and has a poor prognosis. Although the primary tumor in most cases is treated effectively by local surgery or radiotherapy, over 50 % of patients develop systemic metastasis, especially in the liver. In contrast to cutaneous melanoma, there is no standard-of-care treatment for metastasized uveal melanoma. Recently, oncogenic driver mutations in GNAQ or GNA11 were identified in about 85 % of uveal melanomas, which lead to constitutively active signaling in the Gαq/11 pathway and its downstream effectors. Direct targeting of deregulated Gαq/11 signaling might therefore be a therapeutic option for patients with uveal melanoma. In our study we identified the cyclic depsipeptide FR-900359, which is isolated from the evergreen plant Ardisia crenata as an effective inhibitor of constitutively active Gαq/11 proteins and their downstream targets. Although our data are preliminary, they might contribute to a future treatment option for patients with metastasized uveal melanoma.


Assuntos
Melanoma/genética , Neoplasias Uveais/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Humanos , Mutação , Neoplasias Cutâneas
11.
J Dtsch Dermatol Ges ; 18(5): 456-469, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32311823

RESUMO

Skin lesions associated with internal malignancy may present as cutaneous metastases or as typical lesions occurring in the context of certain cancer-associated genetic syndromes. Paraneoplastic syndromes, on the other hand, are only indirectly associated with an underlying malignancy and are not malignant per se. Historically, a distinction has been made between "obligate" and "facultative" paraneoplastic disorders, depending on the likelihood with which they are potentially associated with malignancy. In addition, there are nonspecific cutaneous manifestations that are only rarely associated with an underlying malignancy. Another possible classification is based on the pathophysiological mechanisms underlying the cutaneous lesions. In everyday practice, it is essential that dermatologists recognize potentially cancer-associated dermatoses, as this will frequently contribute to the initial diagnosis of an underlying neoplasm.


Assuntos
Neoplasias/complicações , Dermatopatias/diagnóstico , Dermatopatias/etiologia , Humanos , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/patologia , Neoplasias Cutâneas/secundário
12.
J Dtsch Dermatol Ges ; 18(8): 815-824, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32717116

RESUMO

COVID-19, caused by the coronavirus SARS-CoV-2, has become pandemic. A further level of complexity opens up as soon as we look at diseases whose pathogenesis and therapy involve different immunological signaling pathways, which are potentially affected by COVID-19. Medical treatments must often be reassessed and questioned in connection with this infection. This article summarizes the current knowledge of COVID-19 in the light of major dermatological and allergological diseases. It identifies medical areas lacking sufficient data and draws conclusions for the management of our patients during the pandemic. We focus on common chronic inflammatory skin diseases with complex immunological pathogenesis: psoriasis, eczema including atopic dermatitis, type I allergies, autoimmune blistering and inflammatory connective tissue diseases, vasculitis, and skin cancers. Since several other inflammatory skin diseases display related or comparable immunological reactions, clustering of the various inflammatory dermatoses into different disease patterns may help with therapeutic decisions. Thus, following these patterns of skin inflammation, our review may supply treatment recommendations and thoughtful considerations for disease management even beyond the most frequent diseases discussed here.


Assuntos
COVID-19/complicações , Dermatopatias/etiologia , COVID-19/imunologia , Humanos , Dermatopatias/patologia
20.
J Immunol ; 190(10): 4929-36, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23585676

RESUMO

Epidermal keratinocytes (KCs) and cannabinoid (CB) receptors both participate in the regulation of inflammatory responses in a mouse model for allergic contact dermatitis, the contact hypersensitivity (CHS) response to the obligate sensitizer 2,4-dinitrofluorobenzene. In this study, we investigated the cellular and molecular mechanisms how CB1 receptors attenuate CHS responses to 2,4-dinitrofluorobenzene. We used a conditional gene-targeting approach to identify the relative contribution of CB1 receptors on epidermal KCs for the control of CHS responses. To determine the underlying cellular and molecular mechanisms that regulate inflammatory responses in the effector phase of CHS, we performed further investigations on inflamed ear tissue and primary KC cultures using morphologic, molecular, and immunologic methods. Mice with a KC-specific deletion of CB1 receptors developed increased and prolonged CHS responses. These were associated with enhanced reactive epidermal acanthosis and inflammatory KC hyperproliferation in the effector phase of CHS. In vitro, primary cultures of CB1 receptor-deficient KC released increased amounts of CXCL10 and CCL8 after stimulation with IFN-γ compared with controls. In vivo, contact allergic ear tissue of CB1 receptor-deficient KCs showed enhanced expression of CXCL10 and CCL8 compared with controls. Further investigations established CCL8 as a proinflammatory chemokine regulated by CB1 receptors that promotes immune cell recruitment to allergen-challenged skin. Taken together, these results demonstrate that CB1 receptors are functionally expressed by KCs in vivo and help to limit the secretion of proinflammatory chemokines that regulate T cell-dependent inflammation in the effector phase of CHS.


Assuntos
Quimiocina CCL8/metabolismo , Quimiocina CXCL10/metabolismo , Dermatite Alérgica de Contato/imunologia , Queratinócitos/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transferência Adotiva , Animais , Proliferação de Células , Células Cultivadas , Dermatite Alérgica de Contato/metabolismo , Dinitrofluorbenzeno , Orelha , Inflamação/imunologia , Interferon gama/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA