Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade.
Nat Commun
; 9(1): 2126, 2018 05 29.
Article
em En
| MEDLINE
| ID: mdl-29844427
ABSTRACT
Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model. This effect is T-cell dependent, leading to regression of a significant proportion of tumors. Analysis of tumor lymphocytes demonstrates enhanced effector T-cell and reduced suppressive regulatory T-cell infiltration. Clearance of tumor establishes antigen-specific secondary protective immunity. A synergistic effect of LB-100 and aPD-1 blockade is also observed in B16 melanoma model. In addition, LB-100 activates the mTORC1 signaling pathway resulting in decreased differentiation of naive CD4 cells into regulatory T cells. There is also increased expression of Th1 and decreased expression of Th2 cytokines. These data highlight the translational potential of PP2A inhibition in combination with checkpoint inhibition.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Melanoma Experimental
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Linfócitos do Interstício Tumoral
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Linfócitos T Reguladores
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Neoplasias do Colo
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Compostos Bicíclicos Heterocíclicos com Pontes
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Proteína Fosfatase 2
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Receptor de Morte Celular Programada 1
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Imunoterapia
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Antineoplásicos
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article