Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34183415

RESUMO

The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and nonredundant action of two innate lymphocyte subpopulations, conventional natural killer cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s), is essential for antimetastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 controls metastatic seeding, whereas cNKs restrain outgrowth. Whereas the killing capacity of trILC1s was not affected by the metastatic microenvironment, the phenotype and function of cNK cells were affected in a cancer type-specific fashion. Thus, individual cancer cell lines orchestrate the emergence of unique cNK subsets, which respond differently to tumor-derived factors. Our findings will contribute to the development of therapies for liver metastasis involving hepatic innate cells.


Assuntos
Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Linfócitos/imunologia , Animais , Feminino , Regulação Neoplásica da Expressão Gênica , Integrina alfa1/metabolismo , Interleucina-15/metabolismo , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA-Seq , Análise de Célula Única , Transcriptoma/genética , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
Cell Rep ; 29(5): 1236-1248.e7, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665636

RESUMO

Sensing of cytoplasmic DNA by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) results in production of the dinucleotide cGAMP and consecutive activation of stimulator of interferon genes (STING) followed by production of type I interferon (IFN). Although cancer cells contain supra-normal concentrations of cytoplasmic DNA, they rarely produce type I IFN spontaneously. This suggests that defects in the DNA-sensing pathway may serve as an immune escape mechanism. We find that cancer cells produce cGAMP that is transferred via gap junctions to tumor-associated dendritic cells (DCs) and macrophages, which respond by producing type I IFN in situ. Cancer-cell-intrinsic expression of cGAS, but not STING, promotes infiltration by effector CD8+ T cells and consequently results in prolonged survival. Furthermore, cGAS-expressing cancers respond better to genotoxic treatments and immunotherapy. Thus, cancer-cell-derived cGAMP is crucial to protective anti-tumor CD8+ T cell immunity. Consequently, cancer-cell-intrinsic expression of cGAS determines tumor immunogenicity and makes tumors hot. These findings are relevant for genotoxic and immune therapies for cancer.


Assuntos
Neoplasias/imunologia , Nucleotidiltransferases/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Dano ao DNA , Células Dendríticas/metabolismo , Progressão da Doença , Humanos , Imunoterapia , Interferon Tipo I/metabolismo , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Repetições de Microssatélites/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nucleotídeos Cíclicos/metabolismo
3.
JCI Insight ; 3(10)2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29769439

RESUMO

Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases. Supplementation of mice treated with CSF1R-inhibitor with IL-15 restored numbers of NK cells and diminished metastasis. Our data suggest that CSF1R blockade should be combined with administration of IL-15 to reduce the risk of metastasis.


Assuntos
Células Matadoras Naturais/metabolismo , Células Mieloides/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Linhagem Celular Tumoral , Camundongos
4.
PLoS One ; 9(9): e107355, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25191835

RESUMO

The agouti viable (Avy) locus is considered a model to understand how retroelements function as controlling elements in mammals. Epigenetic factors, principally CpG methylation, are widely held to play a dominant regulatory role in controlling the locus' activity. The purpose of this study was to examine its behavior in ES cells and determine if this locus could be exploited for use in screen-based investigations. We have derived multiple Avy ES cell lines from the C57BL/6 strain and generated a cell line carrying a GFP-reporter gene (Avy/AGFP). Use of the DNA demethylating drug 5-azacitidine on various ES cell lines does not induce either agouti or GFP expression. Methylation analysis reveals that although most lines display normal methylation at IAP elements in general, the Avy IAP element is essentially unmethylated. In addition, we find that different repeat compartments are epigenetically unstable in a number of derived cell lines.


Assuntos
Proteína Agouti Sinalizadora/genética , Metilação de DNA , Células-Tronco Embrionárias/metabolismo , Sequências Reguladoras de Ácido Nucleico , Animais , Linhagem Celular , Células Cultivadas , Regulação para Baixo/genética , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes de Partícula A Intracisternal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sequências Reguladoras de Ácido Nucleico/fisiologia
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa