Tumor-stroma proportion is associated with increased M2 macrophage abundance and predicts the resistance to immune checkpoint blockade in breast cancer.

BACKGROUND: The tumor stroma has been reported to be associated with worse prognosis in several solid tumors, but its prognostic value in breast cancer (BRCA) is still undefined. METHODS: In this research, multiple public and in-house patient cohorts were collected to demonstrate the clinical and immune correlations of tumor-stroma proportion (TSP) in BRCA. In addition, in vitro assays uncovered the oncogenic role of TSP-related collagen in BRCA. RESULTS: High TSP status based on hematoxylin and eosin (HE) staining was associated with positive hormone receptor status, advanced clinical stages, and poor immune checkpoint blockade (ICB) response. In addition, we developed a RNA-sequencing (RNA-seq)-based stromal score based on four critical genes expression (AEBP1, COL6A3, CTSK, and PLAC9). Both TSP status and stromal score were positively associated with increased M2 macrophage abundance in BRCA. Moreover, tumor collagen has been found to be enriched in samples with the high TSP status, and collagen promoted BRCA cells aggressiveness and macrophage M2 polarization. CONCLUSIONS: The tumor stroma was found to be notably related to poor ICB response in patients with BRCA as a result of tumor stroma-macrophage interactions. Thus, the TSP status could predict the clinical outcomes of BRCA patients receiving ICB therapy.