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

  1. Jiaqian Li
  2. Di Huang
  3. Bingxi Lei
  4. Jingying Huang
  5. Linbing Yang
  6. Man Nie
  7. Shicheng Su
  8. Qiyi Zhao
  9. Ying Wang  Is a corresponding author
  1. Sun Yat-sen University, China
  2. 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

Author details

  1. Jiaqian Li

    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Di Huang

    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Bingxi Lei

    Department of Neurosurgery, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Jingying Huang

    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Linbing Yang

    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Man Nie

    Department of Neurosurgery, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Shicheng Su

    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Qiyi Zhao

    Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Ying Wang

    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen University, Guangzhou, China
    For correspondence
    wangy556@mail.sysu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0413-831X

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.

Reviewing Editor

  1. Ping-Chih Ho, Ludwig Institute for Cancer Research, Switzerland

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.

Version history

  1. Received: September 6, 2022
  2. Preprint posted: September 20, 2022 (view preprint)
  3. Accepted: November 24, 2022
  4. Accepted Manuscript published: December 9, 2022 (version 1)
  5. Version of Record published: December 30, 2022 (version 2)
  6. Version of Record updated: January 24, 2023 (version 3)

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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  1. Jiaqian Li
  2. Di Huang
  3. Bingxi Lei
  4. Jingying Huang
  5. Linbing Yang
  6. Man Nie
  7. Shicheng Su
  8. Qiyi Zhao
  9. Ying Wang
(2022)
VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis
eLife 11:e83272.
https://doi.org/10.7554/eLife.83272

Share this article

https://doi.org/10.7554/eLife.83272

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