PD-L1表达是由ERBB3伪激酶域的ATP结合来调节的
Yamu Li1,2, Zhonghua Liu3, Yiqing Zhao1,2
1Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
Genes & diseases
|July 3, 2023
概括
在结直肠癌中,ERBB3伪激酶的ATP结合活性调节PD-L1的表达. ERBB3突变可能预测免疫检查点治疗的反应.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 在癌症中对编程死亡连接体1 (PD-L1) 表达的调节仍然不完全理解.
- 皮表皮生长因子受体 (EGFR) 家族成员ERBB3是一种具有高ATP结合亲和力的伪激酶.
研究的目的:
- 研究ERBB3伪激酶活性在调节大肠直肠癌 (CRC) 中PD-L1基因表达中的作用.
- 阐明将ERBB3与PD-L1调节联系起来的分子机制.
- 评估ERBB3突变作为免疫检查点治疗反应生物标志物的潜力.
主要方法:
- 利用基因工程小鼠模型和CRC细胞系外移植来研究ERBB3功能.
- 评估ERBB3ATP结合失活突变对瘤生长和PD-L1表达的影响.
- 研究了参与ERBB3介导的PD-L1调节的信号通路,包括干扰素- (IFN-γ) 诱导.
- 在小鼠模型中分析了瘤衍生的ERBB3突变对抗PD1抗体治疗反应的影响.
主要成果:
- 在CRC模型中,ERBB3 ATP结合失活显著降低了瘤性和异种移植瘤生长.
- 在ERBB3 ATP结合突变细胞中,IFN-γ诱导的PD-L1表达显著减少.
- 发现ERBB3通过IRS1-PI3K-PDK1-RSK-CREB信号轴调节PD-L1表达,CREB作为关键的转录因子.
- 来自瘤的ERBB3突变的Knockin使小鼠结肠癌对抗PD1抗体治疗敏感.
结论:
- ERBB3伪激酶活性是结直肠癌中PD-L1基因表达的关键调节者.
- 在IRS1-PI3K-PDK1-RSK-CREB路径中介ERBB3的调节PD-L1.
- ERBB3突变代表了患者对免疫检查点抑制剂,特别是抗PD1疗法的反应的潜在预测生物标志物.
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