Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Assunto da revista
Intervalo de ano de publicação
1.
Cancer Cell ; 41(4): 693-710.e8, 2023 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-36963400

RESUMO

Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.


Assuntos
Glioma , Inibidores de Checkpoint Imunológico , Interleucina-8 , Animais , Camundongos , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/patologia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Interleucina-8/metabolismo , Linfócitos T , Microambiente Tumoral
2.
Science ; 369(6506): 984-988, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820125

RESUMO

Germinal center (GC) responses potentiate the generation of follicular regulatory T (TFR) cells. However, the molecular cues driving TFR cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (TFH) cells and T-B cell border-enriched fibroblastic reticular cells, is developmentally required for TFR cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing TFH cells as a distinct T cell population that develops after SOSTDC1- TFH cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in TFH cells results in substantially reduced TFR cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT-ß-catenin axis and facilitates TFR cell differentiation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos B/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Mutantes , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA