Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer.
Cell Death Dis
; 12(11): 1033, 2021 10 30.
Article
em En
| MEDLINE
| ID: mdl-34718325
ABSTRACT
Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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NF-kappa B
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Trato Gastrointestinal
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Proteínas Proto-Oncogênicas c-akt
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Receptor 4 Toll-Like
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Fator 88 de Diferenciação Mieloide
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Microambiente Tumoral
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Antígeno B7-H1
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article