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











Base de datos
Intervalo de año de publicación
1.
J Exp Med ; 215(4): 1091-1100, 2018 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-29511066

RESUMEN

Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function. We hypothesized that 4-1BB signaling might provide metabolic support to tumor-infiltrating T cells. 4-1BB costimulation of CD8+ T cells results in enhanced mitochondrial capacity (suggestive of fusion) and engages PGC1α-mediated pathways via activation of p38-MAPK. 4-1BB treatment of mice improves metabolic sufficiency in endogenous and adoptive therapeutic CD8+ T cells. 4-1BB stimulation combined with PD-1 blockade results in robust antitumor immunity. Sequenced studies revealed the metabolic support afforded by 4-1BB agonism need not be continuous and that a short course of anti-4-1BB pretreatment was sufficient to provide a synergistic response. Our studies highlight metabolic reprogramming as the dominant effect of 4-1BB therapy and suggest that combinatorial strategies using 4-1BB agonism may help overcome the immunosuppressive metabolic landscape of the tumor microenvironment.


Asunto(s)
Inmunoterapia , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Mitocondrias/metabolismo , Biogénesis de Organelos , Linfocitos T/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Anticuerpos/farmacología , Ratones Endogámicos C57BL , Dinámicas Mitocondriales , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/agonistas , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA