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, Chaligné Ronan, Sun Joseph C, Brown Chrysothemis, Pe'er Dana, Boire Adrienne
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Laboratory for Immunology of Metastatic Ecosystems, Center for Cancer Biology, VIB, Leuven, Belgium.
Nature. 2025 May 14. doi: 10.1038/s41586-025-09012-z.
Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours. 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.
转移至充满脑脊液的软脑膜，即软脑膜转移，是实体瘤的一种致命并发症。对临床标本的多模态分析显示，软脑膜转移中存在大量炎症浸润，伴有IFNγ富集及由此产生的下游信号传导。在此，为了研究并克服软脑膜内这种无效的抗肿瘤反应，我们建立了同基因肺癌、乳腺癌和黑色素瘤软脑膜转移小鼠模型。我们发现，缺乏IFNγ或其受体的转基因宿主小鼠无法控制软脑膜转移瘤的生长。通过基于靶向腺相关病毒的系统在软脑膜中过表达Ifng可独立于适应性免疫控制癌细胞生长。利用一系列转基因宿主，我们证明软脑膜T细胞产生IFNγ以积极招募和激活外周髓样细胞，产生多种树突状细胞亚群。独立于抗原呈递，迁移性CCR7树突状细胞协调自然杀伤细胞的流入、增殖和细胞毒性作用，以控制软脑膜中的癌细胞生长。这项研究确定了独特的、软脑膜特异性的IFNγ信号传导，并提出了针对该部位肿瘤的免疫治疗方法。
