Dataset Information

Multi-Modal Profiling Reveals SERPINB3-Driven Immune Evasion and Stromal Immune Mimicry in Triple-Negative Breast Cancer.

ABSTRACT:

Background/objectives

Triple-negative breast cancer (TNBC) exhibits high immune infiltration yet remains clinically aggressive. Although immune checkpoint blockade benefits a subset of patients, the molecular programs enabling concurrent immune activation and immune evasion in TNBC are not fully defined. This study aimed to identify TNBC-specific tumor-intrinsic and tumor-extrinsic molecular features that may explain this paradox.

Methods

Publicly available single-cell RNA-sequencing data from primary breast tumors were analyzed to characterize subtype-specific transcriptional programs across epithelial and stromal compartments. Tumor-intrinsic findings were independently validated using bulk transcriptomic and clinical data from the METABRIC cohort. Tumor microenvironment remodeling was evaluated using multiplexed tissue imaging of TNBC tumors. Functional analyses were done included Gene Ontology enrichment, Hallmark gene set enrichment analysis, and SERPINB3-centered protein-protein interaction network analysis using STRING.

Results

Single-cell analysis identified SERPINB3 as a TNBC-enriched epithelial gene relative to ER+ and HER2+ tumors. This subtype-restricted pattern was validated in the METABRIC cohort and associated with pathways related to epithelial-mesenchymal transition, interferon signaling, and antigen presentation. TNBC tumors also displayed a humoral immune signature characterized by B-cell and plasmablast enrichment, as well as ectopic immunoglobulin gene expression in cancer-associated fibroblasts, endothelial cells, and myeloid populations. Multiplex imaging revealed coordinated associations between immune suppression, stromal activation, and tumor proliferation. Network analysis placed SERPINB3 within interconnected immune-regulatory and stromal signaling modules.

Conclusions

Together, these data indicate that TNBC exhibits co-existing immune activation and immune-suppressive features. The identified epithelial and stromal signatures represent candidate biomarkers that may inform future studies of immune regulation and therapeutic stratification in TNBC.

SUBMITTER: Doha ZO

PROVIDER: S-EPMC12840653 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multi-Modal Profiling Reveals SERPINB3-Driven Immune Evasion and Stromal Immune Mimicry in Triple-Negative Breast Cancer.

Doha Zinab O ZO

Genes 20251231 1

<h4>Background/objectives</h4>Triple-negative breast cancer (TNBC) exhibits high immune infiltration yet remains clinically aggressive. Although immune checkpoint blockade benefits a subset of patients, the molecular programs enabling concurrent immune activation and immune evasion in TNBC are not fully defined. This study aimed to identify TNBC-specific tumor-intrinsic and tumor-extrinsic molecular features that may explain this paradox.<h4>Methods</h4>Publicly available single-cell RNA-sequenc ...[more]

PMID: 41595458

Similar Datasets

Project description:Compared to other subtypes of breast cancer, triple-negative breast cancers (TNBC) have fewer treatment options and exhibit a worse prognosis. Through integrated transcriptomic, metabolomic, immunohistochemical, spatial, and clinical analyses, we identify the mitochondrial enzyme, α-aminoadipate aminotransferase (AADAT) as a previously unrecognized metabolic immune checkpoint in TNBC. AADAT mRNA and protein were significantly upregulated in human TNBC, and high AADAT expression was associated with reduced intra-tumoral CD8⁺ T-cell density and inferior survival. Genetic silencing of AADAT in orthotopic murine TNBC models curtailed primary tumor growth and distant metastasis in a CD8⁺ T-cell–dependent manner, enhanced effector T-cell activation, and sensitized tumors to dual PD-1/CTLA-4 blockade. Mechanistically, unbiased metabolomics showed increased malate levels after AADAT knockdown. Additionally, 4-hydroxyphenylpyruvate, an essential precursor for coenzyme Q₁₀ (CoQ₁₀) biosynthesis, decreased following AADAT knockdown, suggesting an impaired mitochondrial electron transport chain. CoQ₁₀ supplementation restored metabolic balance and reversed malate accumulation caused by AADAT knockdown, indicating that AADAT helps maintain CoQ₁₀-supported redox homeostasis, thereby preventing malate buildup and export. Notably, malate addition directly boosted CD8⁺ T-cell oxidative metabolism, increased the NAD⁺/NADH ratio and reactive oxygen species, and augmented TNF-α and IFN-γ production. In vivo, malate supplementation in drinking water phenocopied AADAT knockdown, restored the response to paclitaxel plus anti–PD-1 therapy in multiple independent syngeneic TNBC models with de novo or acquired resistance to immunotherapy, reduced tumor burden, and prolonged survival. In patient cohorts, higher spatially clustered intra-tumoral malate is associated with co-localization of functional CD8⁺ T cells, decreased exhausted T-cell neighborhoods, and superior post-chemotherapy outcomes. These data position AADAT as a central metabolic orchestrator of immune escape in TNBC and nominate oral malate as a readily translatable adjuvant to reverse chemo-immunotherapy resistance in TNBC.

Dataset Information

Multi-Modal Profiling Reveals SERPINB3-Driven Immune Evasion and Stromal Immune Mimicry in Triple-Negative Breast Cancer.

Background/objectives

Methods

Results

Conclusions

Publications

Multi-Modal Profiling Reveals SERPINB3-Driven Immune Evasion and Stromal Immune Mimicry in Triple-Negative Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets