Uncovering Immune Cell-Specific lncRNAs as Anti-PD-1 Response-Associated Markers in Breast Cancer

Long non-coding RNAs (lncRNAs) are critical regulators of the tumor microenvironment (TME); however, their cell-specific roles in predicting immunotherapy response in breast cancer (BC) remain poorly understood. This study aimed to identify immune cell-specific lncRNA signatures associated with potential pembrolizumab responsiveness by analyzing single-cell RNA sequencing data from 27 BC patients, including luminal and triple-negative (TNBC) subtypes. Differential expression analysis was performed across myeloid, lymphocyte, and dendritic cells, comparing groups based on lymphocyte expansion as a potential responsiveness criterion, classified as lymphocyte clonal expansion (E) and those without or with limited clonal expansion (NE, non-expansion). In luminal patients, potential responsiveness was primarily linked to macrophage-driven lncRNA activity. MUC20-OT1 was upregulated in responders, while LINC01094, a transcript associated with pro-tumoral M2 polarization and immune escape, was elevated in macrophages from non-responders. Conversely, TNBC responders exhibited a lymphocyte-dominant signature, characterized by the upregulation of LINC01871, LINC01943, and MIR4435-2HG. Notably, NEAT1 was uniquely identified as a significantly upregulated marker in dendritic cells of TNBC responders. While NEAT1 is known to modulate T cell abundance and thwart immune evasion in other contexts, its role in BC-associated dendritic cells remains a novel and promising area for investigation. Collectively, these findings demonstrate that lncRNA signatures in the TME are pivotal for understanding pembrolizumab sensitivity. The shift from macrophage-centered lncRNA activity in luminal subtypes to a lymphocyte- and dendritic cell-dominant profile in TNBC underscores the necessity of subtype-specific approaches. These identified lncRNAs emerge as promising candidate biomarkers associated with T cell expansion and potential response to pembrolizumab treatment to refine patient stratification and improve immunotherapeutic outcomes.