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氨酸驱动的YTHDF1表达通过减弱RIG-I调节的免疫反应和增强eIF5B-PD-L1轴来促进膀癌的进展

Anze Yu¹, Liangmin Fu^1,2, Lanyu Jing^3,4

¹Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Cell death and differentiation

|December 13, 2024

概括

氨酸通过减少干扰素信号传递和促进免疫逃避来阻碍膀癌免疫疗法. 在临床前模型中,用型细菌降低 metionin 的含量提高了抗瘤免疫力和生存率.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
代谢过程中的代谢.

背景情况:

氨基酸在瘤免疫治疗中起作用.
氨酸对膀癌免疫疗法的特定影响尚不清楚.

研究的目的:

研究 metionin 影响膀癌免疫疗法的机制.
作为一种治疗策略,探索 metionin 枯竭.

主要方法:

氨基酸查,RNA测序,点突变,小鼠瘤模型 (MB49),单细胞RNA测序.
免疫沉,质谱学,瘤性细菌的静脉注射 (VNP20009).
在人类膀癌患者中进行多重免疫光分析.

主要成果:

氨酸增强了mRNA甲基化,并抑制了膀癌中的I型干扰素 (IFN-I) 途径.
高氨酸会增加YTHDF1的表达,降低RIG-I,并抑制RIG-I/MAVS介导的IFN-I通路.
YTHDF1与eIF5B相互作用,以增强PD-L1的翻译,促进免疫逃避.
在小鼠中,使用VNP20009的局部氨酸消耗延长了生存时间和增强了抗瘤免疫力.
研究结果在人类膀癌患者中得到了验证.

结论:

氨酸通过两种不同的机制抑制膀癌免疫疗法,包括抑制IFN-I通路和增强免疫逃避.
针对性地减少 metionin 的含量是一个有前途的策略,可以提高免疫疗法的疗效,同时对营养造成最小的影响.

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