Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition.
Arseniy E YuzhalinFrank J LoweryYohei SaitoXiangliang YuanJun YaoYimin DuanJingzhen DingSunil AcharyaChenyu ZhangAbigail FajardoHao-Nien ChenYongkun WeiYutong SunLin ZhangYi XiaoPing LiPhilip L LorenziJason T HuseHuihui FanZhong-Ming ZhaoMien-Chie HungDihua YuPublished in: Nature cell biology (2024)
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.
Keyphrases
- cell cycle
- cell proliferation
- single cell
- poor prognosis
- brain metastases
- small cell lung cancer
- resting state
- white matter
- signaling pathway
- high glucose
- type diabetes
- squamous cell carcinoma
- cerebral ischemia
- multiple sclerosis
- case report
- high fat diet induced
- drug induced
- young adults
- insulin resistance
- oxidative stress
- cancer therapy
- adipose tissue
- skeletal muscle
- cell death
- smoking cessation
- replacement therapy