Interferon-γ orchestrates leptomeningeal anti-tumour response

• 成果类型: Article
• 署名作者: Remsik, Jan; Tong, Xinran; Kunes, Russell Z.; Li, Min Jun; Estrera, Rachel; Snyder, Jenna; Thomson, Clark; Osman, Ahmed M.; Chabot, Kiana; Sener, Ugur T.; Wilcox, Jessica A.; Isakov, Danielle; Wang, Helen; Bale, Tejus A.; Chaligne, Ronan; Sun, Joseph C.; Brown, Chrysothemis; Pe'er, Dana; Boire, Adrienne
• 署名单位: Memorial Sloan Kettering Cancer Center; Flanders Institute for Biotechnology (VIB); KU Leuven; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Columbia University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Howard Hughes Medical Institute; Memorial Sloan Kettering Cancer Center; University of California System; University of California San Diego; Karolinska Institutet; Mayo Clinic; Mayo Clinic; Cornell University; Weill Cornell Medicine
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1337
• DOI: 10.1038/s41586-025-09012-z
• 发表日期: 2025-07-24
• 关键词: ifn-gamma; cerebrospinal-fluid; brain; mice; expression; gene; inflammation; macrophages; deletion

摘要

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 IFN gamma 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 IFN gamma 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 IFN gamma 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 IFN gamma signalling and suggests an immune-therapeutic approach against tumours within this space.