Interferon-γ orchestrates leptomeningeal anti-tumour response Journal Article


Authors: Remsik, J.; Tong, X.; Kunes, R. Z.; Li, M. J.; Estrera, R.; Snyder, J.; Thomson, C.; Osman, A. M.; Chabot, K.; Sener, U. T.; Wilcox, J. A.; Isakov, D.; Wang, H.; Bale, T. A.; Chaligné, R.; Sun, J. C.; Brown, C.; Pe’er, D.; Boire, A.
Article Title: Interferon-γ orchestrates leptomeningeal anti-tumour response
Abstract: Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours1. Multimodal analyses of clinical specimens reveal substantial inflammatory infiltrate in leptomeningeal metastases with enrichment of IFNγ and resulting downstream signalling. Here, to investigate and overcome this futile anti-tumour response within the leptomeninges, we developed syngeneic lung cancer, breast cancer and melanoma leptomeningeal-metastasis mouse models. We show that transgenic host mice lacking IFNγ or its receptor fail to control the growth of leptomeningeal metastases growth. Leptomeningeal overexpression of Ifng through a targeted adeno-associated-virus-based system controls cancer cell growth independent of adaptive immunity. Using a suite of transgenic hosts, we demonstrate that leptomeningeal T cells generate IFNγ to actively recruit and activate peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. Independent of antigen presentation, migratory CCR7+ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This study identifies unique, leptomeninges-specific IFNγ signalling and suggests an immune-therapeutic approach against tumours within this space. © The Author(s) 2025.
Journal Title: Nature
Volume: 643
Issue: 8073
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Publication status: Published
Date Published: 2025-07-01
Online Publication Date: 2025-05-14
Start Page: 1087
End Page: 1096
Language: English
DOI: 10.1038/s41586-025-09012-z
PROVIDER: scopus
PMCID: PMC12286854
PUBMED: 40369076
DOI/URL:
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Adrienne Boire -- Source: Scopus
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MSK Authors
  1. Joseph C Sun
    136 Sun
  2. Adrienne Boire
    111 Boire
  3. Dana Pe'er
    112 Pe'er
  4. Tejus Bale
    127 Bale
  5. Ugur Sener
    17 Sener
  6. Jan Remsik
    26 Remsik
  7. Chrysothemis Celia Margaret Brown
    20 Brown
  8. Jessica Alice Wilcox
    37 Wilcox
  9. Danielle Isakov
    7 Isakov
  10. Xinran Tong
    7 Tong
  11. Kiana Chabot
    10 Chabot
  12. Min Jun Li
    7 Li
  13. Jenna M Snyder
    5 Snyder
  14. Russell Kunes
    5 Kunes
  15. Ahmed Mohamed Ahmed Osman
    5 Osman
  16. Helen Wang
    1 Wang