研究动态
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星形胶质细胞诱导的 Cdk5 通过抑制 MHC-I 表达来逃避免疫识别,从而加速乳腺癌脑转移。

Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition.

发表日期:2024 Oct
作者: Arseniy E Yuzhalin, Frank J Lowery, Yohei Saito, Xiangliang Yuan, Jun Yao, Yimin Duan, Jingzhen Ding, Sunil Acharya, Chenyu Zhang, Abigail Fajardo, Hao-Nien Chen, Yongkun Wei, Yutong Sun, Lin Zhang, Yi Xiao, Ping Li, Philip L Lorenzi, Jason T Huse, Huihui Fan, Zhongming Zhao, Mien-Chie Hung, Dihua Yu
来源: NATURE CELL BIOLOGY

摘要:

脑转移瘤 (BrM) 会逃避免疫反应而在大脑中发生,但 BrM 免疫逃避的机制仍不清楚。这项研究表明,脑星形胶质细胞诱导乳腺癌衍生的 BrM 中神经元特异性细胞周期蛋白依赖性激酶 5 (Cdk5) 的过度表达,从而促进小鼠中 BrM 的生长。单细胞 RNA 测序和功能研究证明,Cdk5 过表达 BrM 表现出 I 类主要组织相容性复合体 (MHC-I) 和抗原呈递途径的表达和功能降低,通过遗传或药理学抑制 Cdk5 可恢复这些功能。从机制上讲,Cdk5通过Irf2bp1-Stat1-importin α-Nlrc5途径抑制癌细胞膜上的MHC-I表达,使BrMs能够避免被T细胞识别。单独使用 roscovitine(一种临床适用的 Cdk5 抑制剂)或与免疫检查点抑制剂联合治疗,可显着减轻小鼠的 BrM 负担并增加肿瘤浸润的功能性 CD8 淋巴细胞。因此,星形胶质细胞诱导的 Cdk5 过度表达支持 BrM 免疫逃避,而以 Cdk5 为靶点的治疗可显着提高免疫检查点抑制剂的功效并抑制 BrM 生长。© 2024。作者,获得 Springer Nature Limited 的独家许可。
Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.