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TLR 激动剂可调节 NK 细胞的激活并增强其在急性淋巴细胞白血病中的细胞毒性。

TLR Agonists Modify NK Cell Activation and Increase Its Cytotoxicity in Acute Lymphoblastic Leukemia.

机构信息

Immunology and Proteomics Research Laboratory, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico.

Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City 04360, Mexico.

出版信息

Int J Mol Sci. 2024 Jul 8;25(13):7500. doi: 10.3390/ijms25137500.

DOI:10.3390/ijms25137500
PMID:39000607
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11242025/
Abstract

Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.

摘要

自然杀伤 (NK) 细胞在先天免疫中发挥着至关重要的作用，特别是在对抗感染和肿瘤方面。然而，在血液系统癌症中，NK 细胞通常表现出功能受损。因此，激活其内体 Toll 样受体 (TLR) 作为恢复其抗肿瘤活性的潜在策略非常重要。我们从患有急性淋巴细胞白血病的儿童的外周血单核细胞中刺激 NK 细胞和分离的 NK 细胞，并用特异性 TLR 配体（Poly I:C、Imiquimod、R848 和 ODN2006）刺激 NK 细胞，我们评估了 IFN-γ、CD107a、NKG2D、NKp44 表达、颗粒酶 B 分泌、细胞因子/趋化因子释放和细胞毒性活性的变化。结果表明，Poly I:C 和 Imiquimod 增强了免疫调节和细胞毒性 NK 细胞的激活，增加了 IFN-γ、CD107a、NKG2D 和 NKp44 的表达。R848 激活了免疫调节 NK 细胞，而 ODN2006 增强了细胞毒性 NK 细胞中 CD107a、NKp44、NKG2D 和 IFN-γ 的分泌。R848 还增加了七种细胞因子/趋化因子的分泌。重要的是，R848 和 ODN2006 显著提高了对白血病细胞的细胞毒性。总体而言，TLR 刺激增强了 NK 细胞的激活，表明 TLR8（R848）和 TLR9（ODN2006）配体是抗肿瘤免疫治疗的有前途的候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/9910b1bd2eb4/ijms-25-07500-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/9910b1bd2eb4/ijms-25-07500-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/5bf80887ad14/ijms-25-07500-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/e6fb1b500038/ijms-25-07500-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/f356e1113586/ijms-25-07500-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/2dd313a2f95a/ijms-25-07500-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/c214f97dce35/ijms-25-07500-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5469/11242025/9910b1bd2eb4/ijms-25-07500-g009.jpg

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