Interferon-γ orchestrates leptomeningeal anti-tumour response
Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours<sup>1</sup>. 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<sup>+</sup> 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.
Authors
- Xinran Tong (ORCID: https://orcid.org/0000-0002-8954-1852)
- Danielle Isakov (ORCID: https://orcid.org/0000-0003-4139-8732)
- Minjun Li (ORCID: https://orcid.org/0000-0002-4382-5585)
- Uğur Sener (ORCID: https://orcid.org/0000-0002-3919-7408)
- Kiana Chabot (ORCID: https://orcid.org/0000-0003-2897-0845)
- Tejus Bale (ORCID: https://orcid.org/0000-0003-3641-9287)
- Russell Kunes
- Jessica Wilcox (ORCID: https://orcid.org/0000-0002-2919-1360)
- Jenna Snyder (ORCID: https://orcid.org/0000-0002-5628-5442)
- Ján Remšík (ORCID: https://orcid.org/0000-0002-3228-2896)
- Christopher W. Thomson
- Helen G. Wang (ORCID: https://orcid.org/0000-0003-4407-360X)
- Adrienne Ann Boire (ORCID: https://orcid.org/0000-0002-9029-1248)
- Joseph Chai-Yuen Sun (ORCID: https://orcid.org/0000-0001-8062-9033)
- Dana Pe’er (ORCID: https://orcid.org/0000-0002-9259-8817)
- Ronan Chaligné (ORCID: https://orcid.org/0000-0003-4332-3291)
- Chrysothemis C. Brown (ORCID: https://orcid.org/0000-0002-5834-926X)
- Rachel Estrera (ORCID: https://orcid.org/0009-0006-0772-3641)
- Ahmed M. Osman
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Cornell University (US)
- Karolinska Institutet (SE)
- University of California San Diego (US)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Tri-Institutional PhD Program in Chemical Biology (US)
- New York Institute of Technology (US)
- Mayo Clinic in Arizona (US)
- Weill Cornell Medicine (US)
- Columbia University (US)
- KU Leuven (BE)
Publication Details
- Journal
- Nature
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1038/s41586-025-09012-z
- Citations
- 20
- Primary Topic
- Brain Metastases and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 30.37