Abstract

The infiltration of tumor-infiltrating B cells and plasma cells in early-stage breast cancer has been associated with a reduced risk of distant metastasis. However, the influence of B-cell tumor infiltration on overall patient survival remains unclear. This study explored the relationship between an antitumor immune response, measured by a 14-gene B-cell/immunoglobulin (IGG) signature, and mortality risk in 9638 breast cancer patients across three datasets. Associations with tumor subtype, stage, and age were examined. IGG was characterized using spatial GeoMx profiling and single-cell RNA sequencing, and its relationship with tertiary lymphoid structures (TLSs) was evaluated. The predictive value of each of the 14 IGG genes for B-cell receptor (BCR) and T-cell receptor (TCR) clonality and longevity was also assessed, along with its association with longevity in other cancer types. High IGG signature expression was significantly associated with a 41%-47% reduction in death risk in breast cancer survivors (P < 0.001), regardless of age, tumor stage, or subtype. Similar associations were observed in other cancers, including melanoma. In breast cancer, the IGG signature was significantly linked to overall survival without relapse in patients aged 41-70 years at diagnosis. Additionally, IGG expression correlated with the presence of TLSs and higher B- and T-cell polyclonality. A specific subset of seven IGG genes strongly correlated with BCR and TCR clonality, with predictive power for identifying clonality and improved longevity, especially when combining two of these genes. This study uncovers a significant link between immune gene expression in tumors and extended longevity in breast cancer survivors, even in the absence of recurrence. The IGG signature, particularly its key gene subset, emerges as a powerful marker of sustained antitumor immunity and overall patient fitness. These findings pave the way for personalized treatment strategies that enhance both survival and long-term health outcomes.