美国纪念斯隆-凯特琳癌症中心Adrienne Boire研究组取得一项新突破。他们揭示了干扰素-γ协调脑膜抗肿瘤反应。2025年5月14日出版的《自然》杂志发表了这项成果。

为了研究和克服瘦脑膜内这种无效的抗肿瘤反应，该团队建立了同基因肺癌、乳腺癌和黑色素瘤的瘦脑膜-转移模型。研究人员发现缺乏IFNγ或其受体的转基因宿主小鼠无法控制脑轻脑膜转移瘤的生长。通过靶向腺相关病毒系统，轻脑膜过表达Ifng可独立于适应性免疫控制癌细胞生长。使用一套转基因宿主，小组证明了轻脑膜T细胞产生IFNγ来积极招募和激活外周髓细胞，产生多种树突状细胞亚群。不依赖抗原呈递，迁移的CCR7⁺树突状细胞协调自然杀伤细胞的内流、增殖和细胞毒性作用，以控制肿瘤细胞在脑膜内的生长。本研究确定了独特的，瘦膜生长特异性IFNγ信号，并提出了一种针对该空间肿瘤的免疫治疗方法。

据了解，转移到充满脑脊液的脑脊膜，或称脑脊膜转移，是实体瘤的致命并发症1。临床标本的多模式分析显示，在小脑膜转移瘤中存在大量炎症浸润，IFNγ富集并导致下游信号传导。

附：英文原文

Title: Interferon-γ orchestrates leptomeningeal anti-tumour response

Author: 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., Chalign, Ronan, Sun, Joseph C., Brown, Chrysothemis, Peer, Dana, Boire, Adrienne

Issue&Volume: 2025-05-14

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.

DOI: 10.1038/s41586-025-09012-z

Source: https://www.nature.com/articles/s41586-025-09012-z