Triple-Negative Breast Cancer Shapes the Systemic Immune Landscape and Alters Neutrophil Functionality [bulkRNA-seq]

Cancer dysregulates intratumoral innate-adaptive immune cell crosstalk, but it remains largely unknown how the systemic immune landscape is modified during breast cancer progression. Here, we comprehensively profiled the circulating immune profile of patients with stage I-III or stage IV triple-negative breast cancer (TNBC) and healthy donors (HDs). We showed that patients with metastatic TNBC (mTNBC) exhibited decreased numbers of circulating T cells, dendritic cell subsets and differentiated B cells compared to patients with stage I-III TNBC and HDs, which was partially associated with prior chemotherapy. Moreover, increased IL17 production by vδ1 γδ T cells was observed in patients with mTNBC compared to HDs. Classical monocytes and neutrophils were increased in patients with mTNBC compared to HDs, irrespective of prior chemotherapy. Transcriptional and proteomic analysis, alongside ex vivo functionality assays, revealed increased migratory capacity, increased abundance of granule proteins, and elevated ROS production in circulating neutrophils from mTNBC patients. Some of these systemic immune alterations, including decreased levels of non-switched B cells and increased migratory capacity of neutrophils, were already evident in patients with stage I-III TNBC. Our data underscore the significant impact of TNBC disease stage on the systemic immune composition and function.