RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
NKT 刺激性苯基糖脂与 PEG 化脂质纳米载体配方的生物活性和抗癌活性
英文原题：Bioactivities and Anti-Cancer Activities of NKT-Stimulatory Phenyl-Glycolipid Formulated with a PEGylated Lipid Nanocarrier.
查看英文原题
Bioactivities and Anti-Cancer Activities of NKT-Stimulatory Phenyl-Glycolipid Formulated with a PEGylated Lipid Nanocarrier.
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研究概要
这些发现表明，新配制的 PLN-C34 保留了 C34 的 NKT 刺激活性和抗癌疗效，支持 PLN 作为 C34 溶剂的潜力，以进一步开发用于癌症治疗。
研究思路结论见上方概要
目的
糖脂α-半乳糖神经酰胺（α-GalCer）在由CD1d呈递时，可通过激活自然杀伤T（NKT）细胞调节免疫系统。此前，我们合成了30多种α-GalCer类似物，并鉴定出一种化合物C34，其酰基链上带有两个苯环。C34表现出最强的NKT刺激活性，其特征是在多种小鼠肿瘤模型中具有强烈的Th1偏向性细胞因子和强效抗肿瘤作用。重要的是，与α-GalCer不同，C34不诱导NKT细胞无能。尽管有这些有希望的结果，C34的临床应用因其水溶性差而受到限制。PEG化可增强疏水性药物的溶解度，许多PEG化药物已获得临床批准。因此，在本研究中我们评估了PEG化C34的生物活性。
方法
鼠源NK1.2细胞与A20-CD1d细胞在包载C34的PEG化脂质纳米载体（PLN-C34）或溶于DMSO的C34存在下共培养，通过ELISA测定IL-2产生。C57BL/6小鼠分别经尾静脉注射C34或PLN-C34，采用luminex和流式细胞术检测细胞因子谱和免疫细胞群体。在荷TC-1肺癌和B16黑色素瘤肿瘤的小鼠中评估C34和PLN-C34的抗癌效果。此外，将人PBMCs与C34或PLN-C34共培养，通过luminex测定细胞因子产生。
结果
PLN-C34在体外激活NKT细胞系及体内诱导多种细胞因子方面表现出与C34相当的能力。此外，使用PLN-C34或C34治疗均能显著延长TC-1和B16F10荷瘤小鼠的生存期，且效果相似。另外，PLN-C34能有效刺激人NKT细胞的细胞因子反应，与C34诱导的反应相当。
展开英文摘要原文
PURPOSE
The glycolipid α-galactosylceramide (α-GalCer), when presented by CD1d, can modulate the immune system through the activation of natural killer T (NKT) cells. Previously, we synthesized over 30 analogs of α-GalCer and identified a compound, C34, which features two phenyl rings on the acyl chain. C34 exhibited the most potent NKT-stimulating activities, characterized by strong Th1-biased cytokines and potent anti-tumor effects in several murine tumor models. Importantly, unlike α-GalCer, C34 did not induce NKT cell anergy. Despite these promising results, the clinical application of C34 is limited by its poor aqueous solubility. PEGylation enhances the solubility of hydrophobic drugs, and numerous PEGylated drugs have received clinical approval. Consequently, we assessed the biological activity of PEGylated C34 in this study.
METHODS
Murine NK1.2 cells were cultured with A20-CD1d cells in the presence of either PEGylated lipid nanocarriers encapsulating C34 (PLN-C34) or C34 dissolved in DMSO to determine IL-2 production via ELISA. C57BL/6 mice were i.v. injected with C34 or PLN-C34 to examine cytokine profiles and immune cell populations using luminex and flow cytometry, respectively. The anticancer effects of C34 and PLN-C34 were evaluated in mice bearing TC-1 lung cancer and B16 melanoma tumors. Additionally, human PBMCs were cultured with C34 or PLN-C34 to measure cytokine production through luminex.
RESULTS
PLN-C34 demonstrated a comparable capacity to C34 in activating the NKT cell line in vitro and inducing various cytokines in vivo. Furthermore, treatment with either PLN-C34 or C34 significantly prolonged the survival of TC-1- and B16F10-bearing mice to a similar extent. Additionally, PLN-C34 effectively stimulated cytokine responses in human NKT cells, comparable to those induced by C34.
CONCLUSION
These findings demonstrate that the newly formulated PLN-C34 retains NKT-stimulatory activity and anti-cancer efficacy of C34, supporting the potential of PLN as a solvent for C34 for further development in cancer therapy.
论文信息
- 作者
- Hung JT、Chiou SP、Tang YH、Huang JR、Lo FY、Yu AL
- 单位
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.Taiwan
- 期刊
- Drug design, development and therapy2024
- 原文标识
- PubMed 39583633 · DOI 10.2147/DDDT.S484130
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