Asiaticoside modulates human NK cell functional fate by mediating metabolic flexibility in the tumor microenvironment.
Phytomedicine
; 133: 155921, 2024 Oct.
Article
em En
| MEDLINE
| ID: mdl-39121533
ABSTRACT
BACKGROUND:
Transforming growth factor-beta (TGF-ß), an immunosuppressive cytokine, is often elevated in various tumors and inhibits the immune system's ability to combat tumor cells. Despite promising results from TGF-ß inhibitor therapies, their clinical efficacy remains limited.PURPOSE:
This study aimed to enhance the antitumor capabilities of natural killer (NK) cells in the presence of TGF-ß by exploring the potential of asiaticoside, a natural compound with established clinical safety. STUDYDESIGN:
The effects of asiaticoside on NK cells were investigated to determine its potential to counteract TGF-ß-induced immunosuppression and elucidate the underlying mechanisms.METHODS:
Natural compounds were screened using a Luminex assay to identify those promoting Interferon-γ (IFN-γ) secretion from NK cells. Asiaticoside-pretreated NK cells' cytotoxicity was assessed against K562, OVCAR8, and A2780 cells using organoids from ascites-derived ovarian cancer (OC) cells. In vivo efficacy was evaluated with B16 melanoma lung metastasis and subcutaneous tumor models in C57BL/6 mice, using asiaticoside as a 50 mg/kg injection. The compound's ability to enhance NK cell-driven anti-neoplastic responses was further assessed in an OC murine model. Effects on TGF-ß/SMAD pathways and mitochondrial functions were examined through various microscopy and metabolomic techniques. The involvement of the mTOR/DRP1 axis in asiaticoside-mediated restoration of mitochondrial oxidation in NK cells after TGF-ß suppression was determined using the mTOR inhibitor rapamycin and the DRP1 inhibitor Mdivi-1.RESULTS:
Asiaticoside-treated NK cells retained their ability to suppress tumor growth and metastasis despite TGF-ß presence. Asiaticoside downregulated TGF-ß receptors 1 (TGFBR1) expression, impaired the protein stability of TGFBR1 and TGF-ß receptors 2 (TGFBR2), and reduced SMAD2 phosphorylation, preventing SMAD2 translocation from the mitochondria. This preserved mitochondrial respiration and maintained NK cell antitumor activity.CONCLUSION:
The study concludes that asiaticoside has significant potential as a strategy for "priming" NK cells in cellular immunotherapy. By demonstrating that asiaticoside degrades the TGF-ß receptor, leading to reduced phosphorylation of SMAD2 and preventing its mitochondrial translocation, thereby maintaining mitochondrial integrity. Meantime, asiaticoside counteracts TGF-ß-induced suppression of mitochondrial oxidative and aerobic respiration through the mTOR/DRP1 pathways. The research uncovers a previously unreported pathway for preserving mitochondrial respiration and NK cell functionality. A detailed mechanistic insight into how asiaticoside functions at the molecular level was explored. Its ability to counteract the immunosuppressive effects of TGF-ß makes it a valuable candidate for enhancing the effectiveness of immunotherapies in treating a variety of tumors with elevated TGF-ß levels.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triterpenos
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Células Matadoras Naturais
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Fator de Crescimento Transformador beta
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Serina-Treonina Quinases TOR
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Microambiente Tumoral
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Camundongos Endogâmicos C57BL
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article