Linking tumor immune infiltration to enhanced longevity in recurrence-free breast cancer

Abstract

Breast cancer; Immune gene expression; Longevity

Càncer de mama; Expressió gènica immune; Longevitat

Cáncer de mama; Expresión génica inmune; Longevidad

Background 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. Materials and methods 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. Results 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. Conclusions 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.

LA received funding from Instituto de Salud Carlos III CM20/00091. FS is supported by a Rio Hortega clinical scientist contract from the Instituto de Salud Carlos III CM20/00073. CMP received funding from the Breast Cancer Research Foundation (BCRF-23-127) and the NCI Breast SPORE program (P50-CA058223). AP received funding from the Breast Cancer Research Foundation (BCRF-22-198 and BCRF-23-198), Beca Marta Santamaría, Fundación CRIS contra el Cancer PR_EX_2021-14, Agència de Gestó d’Ajuts Universitaris I de Recerca 2021 SGR 01156, Fundación Fero BECA ONCOXXI21, Asociación Cáncer de Mama Metastásico IV Premios M. Chiara Giorgetti, PI22/01017: funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, and RESCUER: funded by European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 847912. FBM received funding from Fundación científica AECC Ayudas Investigador AECC 2021 (INVES21943BRAS) and Fundación Contigo Contra el Cancer de Mama de la Mujer (HIMALAIA). Figures 1A and 3G were produced by Antonio García, scientific illustrator from Bio-Graphics.