Interferon-γ orchestrates leptomeningeal anti-tumour response

Jan Remsik, Xinran Tong, Russell Z. Kunes, Min Jun Li, Rachel Estrera, Jenna Snyder, Clark Thomson, Ahmed M. Osman, Kiana Chabot, Ugur T. Sener, Jessica A. Wilcox, Danielle Isakov, Helen Wang, Tejus A. Bale, Ronan Chaligné, Joseph C. Sun, Chrysothemis Brown, Dana Pe’er and Adrienne Boire ()
Additional contact information
Jan Remsik: Memorial Sloan Kettering Cancer Center
Xinran Tong: Memorial Sloan Kettering Cancer Center
Russell Z. Kunes: Memorial Sloan Kettering Cancer Center
Min Jun Li: Memorial Sloan Kettering Cancer Center
Rachel Estrera: Memorial Sloan Kettering Cancer Center
Jenna Snyder: Memorial Sloan Kettering Cancer Center
Clark Thomson: Memorial Sloan Kettering Cancer Center
Ahmed M. Osman: Memorial Sloan Kettering Cancer Center
Kiana Chabot: Memorial Sloan Kettering Cancer Center
Ugur T. Sener: Memorial Sloan Kettering Cancer Center
Jessica A. Wilcox: Memorial Sloan Kettering Cancer Center
Danielle Isakov: Memorial Sloan Kettering Cancer Center
Helen Wang: Memorial Sloan Kettering Cancer Center
Tejus A. Bale: Memorial Sloan Kettering Cancer Center
Ronan Chaligné: Memorial Sloan Kettering Cancer Center
Joseph C. Sun: Memorial Sloan Kettering Cancer Center
Chrysothemis Brown: Memorial Sloan Kettering Cancer Center
Dana Pe’er: Memorial Sloan Kettering Cancer Center
Adrienne Boire: Memorial Sloan Kettering Cancer Center

Nature, 2025, vol. 643, issue 8073, 1087-1096

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09012-z

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