Systems immunology insights into brain metastasis

Abstract

Brain metastasis poses formidable clinical challenges due to its intricate interactions with the brain's unique immune environment, often resulting in poor prognoses. This review delves into systems immunology's role in uncovering the dynamic interplay between metastatic cancer cells and brain immunity. Leveraging spatial and single-cell technologies, along with advanced computational modeling, systems immunology offers unprecedented insights into mechanisms of immune evasion and tumor proliferation. Recent studies highlight potential immunotherapeutic targets, suggesting strategies to boost antitumor immunity and counteract cancer cell evasion in the brain. Despite substantial progress, challenges persist, particularly in accurately simulating human conditions. This review underscores the need for interdisciplinary collaboration to harness systems immunology's full potential, aiming to dramatically improve outcomes for patients with brain metastasis.

Keywords: blood–brain barrier; brain metastasis; computational modeling; single-cell analysis; spatial technologies; systems immunology; tumor–immune cell interactions.

Key figure, Figure 1.

Schematic of systemic immunology in brain metastasis. Multi-omic data from brain metastatic tumor samples are generated through high-throughput profiling techniques such as genomics, transcriptomics, proteomics, metabolomics, and spatial omics profiling. These data are analyzed using various computational tools and models, (detailed in the bottom left box) which include Seurat, Scanpy, Squidpy, and others for cell type annotation, cell-specific gene expression, cell transcriptomic trajectory, and cell-cell communication (bottom right box). Output analyses can lead to clinical translation, focusing on biomarker discovery, identification of novel targets such as tumor cells, immune cells, and their interactions, as well as predictions of drug combination efficacy and treatment outcomes. This figure was created using BioRender.com.

Figure 2.

Microglial dynamics during brain metastasis. Microglia respond to brain metastatic tumor cells in patients by upregulating a pro-inflammatory program (IFN response, antigen presenting (AP) and cytokine-secretory) that promote anti-tumor CD4⁺, CD8⁺ and NK cell responses and tumor regression in the brain [1]. In a CX3CR1^-high, PD-L1⁺/VISTA^-high microglia-enriched tumor microenvironment (TME) in animal models (e.g. mice), NK and T cell responses are deficient and the proportion of Tregs is increased, resulting in tumor progression [9]. This figure was created using BioRender.com.

Figure 3.

NK cell dynamics in brain metastasis. NK cells, primarily localized in the meninges, exhibit direct cytotoxicity against tumor cells and activate T cells and astrocytes through the secretion of IFN-γ to combat metastasis. NK cell-derived IFN-γ induces TRAIL expression in astrocytes, promoting tumor apoptosis but also T cell apoptosis to limit neuroinflammation [37]. This regulatory mechanism provides a basis for therapeutic interventions that could manipulate these interactions to enhance anti-tumor immunity while controlling inflammation. This figure was created using BioRender.com.