Delivery of toll-like receptor agonists by complement C3-targeted liposomes activates immune cells and reduces tumour growth.
Delivery of toll-like receptor agonists by complement C3-targeted liposomes activates immune cells and reduces tumour growth.
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DOI：
10.1080/1061186x.2021.1878364
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发表时间：
2021-08
影响因子：
4.5
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中科院分区：
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抗原提呈细胞（APCs）的激活是免疫识别和消除癌症的必要条件。我们的实验室已经开发出一种脂质体纳米颗粒，可以结合血清中存在的补体C3蛋白。这些c3脂质体被apc和其他表达补体c3结合受体的髓细胞特异性内化。已知的免疫刺激化合物toll样受体（TLR）激动剂被包裹在c3脂质体中，包括分别针对TLR4、TLR7/8和TLR9特异性的单磷酰脂质A （MPLA）、R848和CpG 1826。当被髓细胞内各自的tlr识别时，这些化合物触发信号级联反应，最终导致炎症细胞因子和激活标志物（CD80、CD83、CD86和CD40）的表达增加。对c3脂质体处理的小鼠骨髓细胞进行RT-PCR分析发现，促炎细胞因子和因子（IL-1β、IL-6、IL-12、TNF-α、IRF7和IP-10）的基因表达显著增加。此外，与PBS处理的小鼠相比，用含有TLR激动剂的c3脂质体治疗4T1荷瘤小鼠导致肿瘤生长减少。总之，这些结果表明，在乳腺癌模型中，c3脂质体递送TLR激动剂激活apc并诱导肿瘤特异性适应性免疫反应，导致肿瘤生长减少。
Activation of antigen presenting cells (APCs) is necessary for immune recognition and elimination of cancer. Our lab has developed a liposome nanoparticle that binds to complement C3 proteins present in serum. These C3-liposomes are specifically internalised by APCs and other myeloid cells, which express complement C3-binding receptors. Known immune stimulating compounds, toll-like receptor (TLR) agonists, were encapsulated within the C3-liposomes, including monophosphoryl lipid A (MPLA), R848, and CpG 1826, specific for TLR4, TLR7/8, and TLR9 respectively. When recognised by their respective TLRs within the myeloid cells, these compounds trigger signal cascades that ultimately lead to increased expression of inflammatory cytokines and activation markers (CD80, CD83, CD86 and CD40). RT-PCR analysis of murine bone marrow cells treated with C3-liposomes revealed a significant increase in gene expression of pro-inflammatory cytokines and factors (IL-1β, IL-6, IL-12, TNF-α, IRF7, and IP-10). Furthermore, treatment of 4T1 tumour-bearing mice with C3-liposomes containing TLR agonists resulted in reduced tumour growth, compared to PBS treated mice. Collectively, these results demonstrate that C3-liposome delivery of TLR agonists activates APCs and induces tumour-specific adaptive immune responses, leading to reduced tumour growth in a breast cancer model.