2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.12: Extracellular Matrix Remodeling and Immune Evasion Drive Lung Adenocarcinoma Brain Metastasis

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The study explores the unique extracellular matrix (ECM) and immune environment associated with brain metastases (BrM) in patients with non-small cell lung cancer (NSCLC), which occur in 30% of cases and significantly worsen prognosis and quality of life. Immunotherapy shows limited efficacy (15-40%) for these metastases compared to primary lung tumors. Despite previous analyses of paired lung tumors and brain metastases, comprehensive transcriptomic studies throughout the metastatic process remain scarce.<br /><br />Data from 22 patients with matched samples (normal lung, primary lung adenocarcinoma tumor, and brain metastasis) were utilized to investigate ECM and immune environment changes driving NSCLC brain metastasis. Key findings suggest that coordinated ECM remodeling and immune evasion critically contribute to metastasis formation. A combination therapy targeting both components may reduce brain metastasis risk in lung adenocarcinoma.<br /><br />Hierarchical clustering of ECM and immune genes from the TCGA-LUAD cohort identified two patient groups with distinct gene sets: ECM and immune genes. Group 1, characterized by lower expression of these genes, included more late-stage patients and was linked to poorer outcomes, specifically in Stage III. Notably, a 349 gene ECM-immune signature was prognostic for Stage III patients.<br /><br />The transcriptomic landscape analysis showed 163 genes differentially expressed between transition phases (normal lung to primary lung tumor to brain metastasis), with common downregulated pathways in brain metastases involving ECM organization, immune response, and T-cell activation. Specific gene markers identified included HAPLN2 and SERPINA3 upregulated in brain metastases, and tumor-specific markers PRAME and HOXC10.<br /><br />Overall, the study emphasizes the significant role of ECM and immune alterations in NSCLC metastasis to the brain, underscoring the potential benefits of targeted therapeutic strategies.

Asset Subtitle

Manlu Liu

Keywords

extracellular matrix

immune environment

brain metastases

non-small cell lung cancer

immunotherapy

transcriptomic studies

ECM remodeling

immune evasion

gene signature

therapeutic strategies