Brain Metastases Immune Microenvironment [Neurosurgery Wiki]

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====== Brain Metastases Immune Microenvironment ======

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1FuuOtUS4LZ28-VurliWhL9_59y1r9-9g0nNardLbt28y64986/?limit=15&utm_campaign=pubmed-2&fc=20250504102814}}

**Definition**  

The [[brain metastases]] (BrM) [[immune microenvironment]] refers to the **cellular and molecular [[composition]] of [[immune cell]]s** within and around metastatic tumors that have spread to the [[brain]]. It includes both the **type and spatial distribution** of immune cells, as well as the **local immune activity and suppressive signals**.

=== Unique Features of the Brain Microenvironment ===
  * The **blood-brain barrier (BBB)** limits immune cell trafficking
  * The brain has a distinct **immune surveillance system**, including microglia and perivascular macrophages
  * BrM can remodel the local environment, attracting or excluding systemic immune cells

=== Key Immune Components ===
  * **CD8+ T cells** – cytotoxic lymphocytes that may infiltrate or be excluded from tumor parenchyma  
  * **CD4+ T cells and regulatory T cells (Tregs)** – modulate immune responses and may promote immune evasion  
  * **Tumor-associated macrophages (TAMs)** – often immunosuppressive in the CNS  
  * **Dendritic cells and B cells** – participate in antigen presentation and may contribute to local TLS formation  

=== Recent Findings ===
  * [[Transcriptome-wide gene expression profiling]] and [[spatial immune cell profiling]] have revealed that BrM from [[lung cancer]] and [[melanoma]] exhibit **higher immune cell infiltration** than those from [[breast cancer]]  
  * Presence of [[tertiary lymphoid structure]]s (TLS) has been detected in some BrM, especially in treatment-naïve lung and melanoma metastases  
  * TLS presence is associated with **prolonged survival** and may serve as a **prognostic biomarker** in BrM  

=== Clinical Relevance ===
  * BrM TIME influences **response to immunotherapy**  
  * Immune "hot" BrM (high infiltration and TLS presence) may respond better to **immune checkpoint blockade**  
  * Understanding the TIME helps stratify patients and guide CNS-targeted immunotherapies  

=== Research Techniques Used ===
  * [[RNA sequencing-based immune cell deconvolution]]  
  * [[Multiplex immunofluorescence staining]]  
  * [[Spatial immune cell profiling]]  
  * IHC for markers like CD3, CD8, CD20, PD-L1  


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Mughal et al. and [[Katrin Lamszus]] from the laboratory for [[Brain Tumor Biology]], Department of Neurosurgery, University Medical Center Hamburg-Eppendorf,  Germany performed [[transcriptome-wide gene expression profiling]] combined with [[spatial immune cell profiling]] to characterize the [[tumor immune microenvironment]] in 95 patients with BrM from different [[primary tumor]]s. 
They found that BrM from [[lung cancer]] and malignant [[melanoma]] showed overall higher [[immune cell infiltration]] as compared to BrM from [[breast cancer]]. [[RNA sequencing-based immune cell deconvolution]] revealed [[gene expression]] [[signature]]s indicative of [[tertiary lymphoid structure]]s (TLS) in subsets of BrM, mostly from lung cancer and melanoma. This finding was corroborated by [[multiplex immunofluorescence staining]] of [[immune cell]]s in BrM tissue sections. Detection of TLS signatures was more common in [[treatment]]-naïve BrM and associated with prolonged [[survival]] after [[Brain metastases diagnosis]] in [[lung cancer]] patients. 
The findings highlight the cellular [[diversity]] of the [[tumor immune microenvironment]] in BrM of different [[cancer]] types and suggest a role of TLS formation for BrM [[patient outcome]]
((Mughal SS, Reiss Y, Felsberg J, Meyer L, Macas J, Schlue S, Starzetz T, Köhrer K, Fehm T, Müller V, Lamszus K, Schadendorf D, Helfrich I, Wikman H, Berghoff A, Brors B, Plate KH, Reifenberger G. [[Identification]] and [[characterization]] of [[tertiary lymphoid structure]]s in [[brain metastases]]. Acta Neuropathol Commun. 2025 May 3;13(1):91. doi: 10.1186/s40478-025-02007-x. PMID: 40319321.))
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Mughal et al. conducted a comprehensive study combining [[transcriptome-wide gene expression profiling]] with [[spatial immune cell profiling]] in 95 patients with [[brain metastases]] (BrM) from various [[primary tumor]] origins. Their goal was to better understand the heterogeneity of the [[tumor immune microenvironment]] (TIME) in BrM and its potential clinical implications.

=== Strengths ===
  * **Multimodal approach**: The integration of RNA sequencing with spatial techniques provides both molecular and spatial resolution, offering a robust characterization of immune landscapes.
  * **Cohort diversity**: Inclusion of BrM from multiple cancer types (lung, melanoma, breast) allows for cross-comparison and subtype-specific insights.
  * **Novel findings**: Identification of [[tertiary lymphoid structure]] (TLS) signatures in BrM, especially from lung and melanoma, adds valuable data to the field and supports the idea that TLS may serve as a **biomarker** for favorable [[patient outcome]].
  * **Clinical relevance**: The association of TLS presence with **prolonged survival** in treatment-naïve lung cancer BrM patients is particularly significant and hypothesis-generating for future therapeutic targeting.

=== Limitations ===
  * **Lack of functional validation**: While TLS presence was inferred via [[RNA sequencing-based immune cell deconvolution]] and confirmed with [[multiplex immunofluorescence staining]], functional studies to prove TLS immunological activity (e.g., antigen presentation, T/B cell interaction) are lacking.
  * **Cross-sectional design**: The study is primarily descriptive and cross-sectional; longitudinal tracking of TLS development or dynamic changes in TIME over treatment is not addressed.
  * **Heterogeneity within tumor types**: Although BrM from lung and melanoma were grouped together, their internal heterogeneity (e.g., EGFR-mutant vs. KRAS-mutant lung cancer) may influence immune profiles and was not deeply stratified.
  * **Limited exploration of immune suppression**: The study focuses on immune infiltration and TLS, but immunosuppressive elements of the TIME (e.g., Tregs, myeloid-derived suppressor cells) are not fully explored.

=== Conclusion ===
This study significantly advances our understanding of the immune contexture of brain metastases, emphasizing the **variability between tumor types** and the potential prognostic role of [[tertiary lymphoid structure]]s. Mughal et al. provide a strong foundation for future work aiming to **modulate immune niches** within BrM, especially in the context of immunotherapy. However, the **mechanistic role** of TLS in anti-tumor immunity within the CNS remains to be elucidated, and follow-up studies should address **temporal dynamics**, **TLS function**, and **response to therapy**.