VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis

作者：Jiaqian Li, Di Huang, Bingxi Lei, Jingying Huang, Linbing Yang, Man Nie, Shicheng Su, Qiyi Zhao, Ying Wang · 发表于：eLife · 年份：2022 · DOI：10.7554/elife.83272 · 被引用次数：13 · 研究领域：Brain Metastases and Treatment、Glioma Diagnosis and Treatment、Neuroinflammation and Neurodegeneration Mechanisms

Leptomeningeal metastasis is associated with dismal prognosis and has few treatment options. However, very little is known about the immune response to leptomeningeal metastasis. Here, by establishing an immunocompetent mouse model of breast cancer leptomeningeal metastasis, we found that tumor-specific CD8 + T cells were generated in deep cervical lymph nodes (dCLNs) and played an important role in controlling leptomeningeal metastasis. Mechanistically, T cells in dCLNs displayed a senescence phenotype and their recruitment was impaired in mice bearing cancer cells that preferentially colonized in leptomeningeal space. Upregulation of p53 suppressed the transcription of VLA-4 in senescent dCLN T cells and consequently inhibited their migration to the leptomeningeal compartment. Clinically, CD8 + T cells from the cerebrospinal fluid of patients with leptomeningeal metastasis exhibited senescence and VLA-4 downregulation. Collectively, our findings demonstrated that CD8 + T cell immunosenescence drives leptomeningeal metastasis.