在GCN2 Null小鼠中,聚胺阻断疗法对抗瘤有效性的损失
Eric T Alexander1, Erin Fahey1, Otto Phanstiel2
1Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
Biomedicines
|October 28, 2023
概括
聚胺和氨酸代谢激活GCN2,促进瘤生长和免疫抑制. 聚胺阻断疗法 (PBT) 通过向GCN2来抑制瘤,从而影响髓质衍生抑制细胞和巨细胞.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 代谢途径 代谢途径
背景情况:
- 一般控制不可抑制的2 (GCN2) 激酶感知氨基酸饥饿.
- 瘤微环境激活GCN2,有助于瘤的生存和进展.
- 多氨酸和氨酸代谢与瘤生长和免疫逃避有关.
研究的目的:
- 调查聚胺生物合成和氨酸枯竭是否激活GCN2.
- 为了确定聚胺阻断疗法 (PBT) 的有效性是否依赖于GCN2抑制.
- 阐明GCN2在瘤微环境中的骨髓原抑制细胞 (MDSC) 和巨细胞中的作用.
主要方法:
- 使用了GCN2淘汰和野生型小鼠与同源B16.F10或EG7瘤.
- 使用聚胺阻断疗法 (PBT) 来评估抗瘤疗效.
- 分析了小鼠骨髓细胞培养物以研究聚胺代谢,氨酸枯竭,GCN2激活,MDSC生成,自和巨两极分化.
主要成果:
- 与野生类型小鼠不同的是,PBT未能抑制GCN2淘汰赛小鼠的瘤生长.
- 在野生型小鼠中,PBT治疗改变了透免疫细胞的形状,但并没有改变GCN2淘汰小鼠的形状.
- 氨酸枯竭和GCN2激活对于MDSC生成,细胞保护性自,M2巨两极分化和生存至关重要,所有这些都是由PBT抑制的.
结论:
- 聚胺依赖的GCN2信号传递在 stromal 细胞中驱动瘤生长和免疫抑制.
- 通过向GCN2,PBT至少部分具有抗瘤作用.
- 在瘤微环境中,GCN2在调节免疫细胞功能方面发挥着至关重要的作用.
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