Background:
Dendritic cells (DCs) orchestrate anti-tumour immunity by initiating and regulating adaptive immune responses, yet their functional heterogeneity in early breast cancer (EBC) remains incompletely understood. Mature regulatory dendritic cells (mregDCs) represent an antigen experienced DC state characterised by coordinated activation and immunoregulation. However, their distribution, mechanisms of induction and clinical significance in EBC remain poorly defined.
Methods:
We performed multi-compartment immune profiling of treatment-naïve EBC using high-dimensional flow cytometry of tumour tissue, tumour-draining lymph nodes (LNs) and peripheral blood from 125 patients and 16 healthy volunteers. Mechanisms of mregDC differentiation were investigated using autologous and allogeneic tumour PBMC co-culture models. Associations with molecular subtype, pathological response following neoadjuvant chemotherapy (NACT) and ethnicity were examined and validated using the SCAN B (n = 2,929) and BrighTNess (n = 634) transcriptomic datasets.
Results:
CCR7⁺ mregDCs were enriched in tumours and tumour-draining LNs compared with peripheral blood. Tissue-resident mregDCs displayed an activated immunoregulatory phenotype with increased CD83, CD40, CD86, PD-L1 and PD-L2 expressions. Across independent transcriptomic cohorts, elevated mregDC signatures were associated with improved survival in immunogenic breast cancer subtypes and predicted pathological complete response following NACT in triple negative breast cancer. Circulating mregDC associated phenotypes were enriched in triple-negative breast cancer, accompanied by an inflammatory systemic cytokine milieu, and showed a trend towards increased abundance in patients achieving pathological complete response. Autologous tumour PBMC co cultures induced the mregDC programme, whereas the capacity of circulating precursors to differentiate into mregDCs progressively declined with disease advancement, suggesting loss of dendritic cell plasticity.
Conclusions:
mregDCs represent a conserved antigen experienced DC state associated with effective anti tumour immunity in EBC. Their enrichment within tumour associated tissues, association with favourable clinical outcomes, inducibility by tumour derived signals and progressive functional impairment during disease progression support their potential as biomarkers of immune engagement and therapeutic response.