Nature Cell Biology ( IF 17.3 ) Pub Date : 2024-09-20 , DOI: 10.1038/s41556-024-01509-5 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
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.
中文翻译:
星形胶质细胞诱导的 Cdk5 通过抑制 MHC-I 表达逃避免疫识别来加速乳腺癌脑转移
脑转移 (BrM) 逃避了在大脑中产生的免疫反应,但 BrM 免疫逃避的机制仍不清楚。这项研究表明,脑星形胶质细胞在乳腺癌来源的 BrM 中诱导神经元特异性细胞周期蛋白依赖性激酶 5 (Cdk5) 的过表达,从而促进小鼠 BrM 的生长。Cdk5 过表达的 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,这些途径通过遗传或药理学抑制 Cdk5 来恢复,单细胞 RNA 测序和功能研究证明了这一点。从机制上讲,Cdk5 通过 Irf2bp1-Stat1-importin α-Nlrc5 通路抑制癌细胞膜上的 MHC-I 表达,使 BrMs 能够避免被 T 细胞识别。Roscovitine - 一种临床适用的 Cdk5 抑制剂 - 单独或与免疫检查点抑制剂联合治疗,可显着降低小鼠的 BrM 负荷并增加肿瘤浸润功能性 CD8 + 淋巴细胞。因此,星形胶质细胞诱导的 Cdk5 过表达支持 BrM 免疫逃避,而治疗性靶向 Cdk5 显着提高了免疫检查点抑制剂的疗效并抑制了 BrM 生长。