VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis
- Sun Yat-sen University, China
- Third Affiliated Hospital of Sun Yat-sen University, China
Abstract
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 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figure 4G and Figure supplement 4I.
Article and author information
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Funding
Natioanl Key Research and Development Program of China (021YFA1300502)
- Shicheng Su
Natural Science Foundation of China (82002786)
- Linbing Yang
Natural Science Foundation of China (82003859)
- Man Nie
Natural Science Foundation of Guangdong Province (2020A1515011)
- Di Huang
Natural Science Foundation of Guangdong Province (2022B1515020023)
- Qiyi Zhao
Natural Science Foundation of Guangdong Province (2021A1515010230)
- Linbing Yang
Science and Technology Program of Guangzhou (202103000070)
- Shicheng Su
Science and Technology Program of Guangzhou (202201020467)
- Qiyi Zhao
Sun Yat-Sen Projects for Clinical Trials (SYS-C-20200)
- Ying Wang
Fundamental Research Funds for the Central Universities (22ykqb01)
- Qiyi Zhao
Natural Science Foundation of China (1942309)
- Shicheng Su
Natural Science Foundation of China (2057210)
- Shicheng Su
Natural Science Foundation of China (8222202)
- Di Huang
Natural Science Foundation of China (8207175)
- Ying Wang
Natural Science Foundation of China (8227179)
- Ying Wang
Natural Science Foundation of China (81971481)
- Qiyi Zhao
Natural Science Foundation of China (82173064)
- Qiyi Zhao
Natural Science Foundation of China (81602205)
- Bingxi Lei
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were bred and maintained in the specific-pathogen-free (SPF) animal facility of the Laboratory Animal Center of Sun Yat-Sen University. All procedures were approved by the Animal Care and Use Committee of Sun Yat-Sen University under animal protocol 2018-000095 and 2021-000768).
Human subjects: All samples were collected with informed consents, and all related procedures were performed with the approval of the internal review and ethics board of Sun Yat-Sen Memorial Hospital under protocol 2020-136.
Copyright
© 2022, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis
eLife 11:e83272.
https://doi.org/10.7554/eLife.83272
