Leptomeningeal anti-tumor immunity follows unique signaling principles

Abstract

Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-gamma signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-gamma or its receptor, fail to control LM growth. Overexpression of Ifn-gamma through a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-gamma actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-gamma signaling and suggests a novel immune-therapeutic approach against tumors within this space.

The covariance environment defines cellular niches for spatial inference

“…Mice were housed in specific pathogen-free conditions, in an environment with controlled temperature and humidity, on a 12-h light/dark cycle (lights on/off at 6:00/18:00), and with access to regular chow and sterilized tap water ad libitum. For this study, an 8-week-old female C57Bl/6-Tyr c-2 mouse (The Jackson Laboratory, 000058, albino C57Bl/6) was injected with 500 B16 LeptoM cells intracisternally, as described in Remsik et al 74 . Two weeks after the injection, the mouse was deeply anaesthetized and transcardially perfused with PBS (MSK Media Core).…”

“…The poor understanding of interactions among tumor, immune and underlying brain parenchyma cells limits the discovery of therapeutics. We used the Xenium platform (10x Genomics) 16 to perform in situ hybridization (ISH) of 243 genes in a mouse model of melanoma LM 74 and also sequenced cells from an adjacent section using a custom single-nucleus RNA sequencing (snRNA-seq) protocol (Methods) that we developed by optimizing RNA extraction from formalin-fixed paraffin-embedded (FFPE) samples, followed by 10x Genomics Flex probe-based library preparation. We separately clustered and annotated the spatial and single-cell samples into major cell types based on marker genes (Fig.…”

“…Melanoma LM interacts with two key immune populations: tissue-resident brain macrophages, known as microglia, and monocyte-derived macrophages that are recruited to the tumor lesion and colonize it from the periphery 74 . The snRNA-seq data clearly distinguish these myeloid subtypes based on curated gene sets 75 , whereas the Xenium brain panel lacks the markers to distinguish macrophages and microglia (Fig.…”