Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Nat Cell Biol. 2024 Oct;26(10):1773-1789. doi: 10.1038/s41556-024-01509-5. Epub 2024 Sep 20.
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.
脑转移瘤（BrMs）逃避免疫反应在大脑中发展，但 BrM 免疫逃逸的机制仍不清楚。本研究表明，脑星形胶质细胞在乳腺癌来源的 BrMs 中诱导神经元特异性细胞周期蛋白依赖性激酶 5（Cdk5）的过度表达，这促进了 BrM 在小鼠中的生长。Cdk5 过表达的 BrMs 表现出降低的 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，通过遗传或药理学抑制 Cdk5 可恢复这些功能，这可通过单细胞 RNA 测序和功能研究得到证明。在机制上，Cdk5 通过 Irf2bp1-Stat1-importinα-Nlrc5 途径抑制癌细胞膜上的 MHC-I 表达，使 BrMs 逃避 T 细胞的识别。用罗西维林——一种临床应用的 Cdk5 抑制剂——单独或与免疫检查点抑制剂联合治疗，可显著减少小鼠 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 免疫逃逸，而靶向 Cdk5 的治疗可显著提高免疫检查点抑制剂的疗效并抑制 BrM 的生长。
