PAK4 inhibition improves PD-1 blockade immunotherapy.
Nat Cancer
; 1(1): 46-58, 2020.
Article
em En
| MEDLINE
| ID: mdl-34368780
ABSTRACT
Lack of tumor infiltration by immune cells is the main mechanism of primary resistance to programmed cell death protein 1 (PD-1) blockade therapies for cancer. It has been postulated that cancer cell-intrinsic mechanisms may actively exclude T cells from tumors, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. Here, we show that p21-activated kinase 4 (PAK4) is enriched in non-responding tumor biopsies with low T cell and dendritic cell infiltration. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD-1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of anti-PD-1 with the PAK4 inhibitor KPT-9274 improved anti-tumor response compared with anti-PD-1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and a lack of response to PD-1 blockade, which could be reversed with PAK4 inhibition.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinases Ativadas por p21
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Receptor de Morte Celular Programada 1
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Inibidores de Checkpoint Imunológico
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Imunoterapia
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Neoplasias
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article