CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Axillary lymph nodes are primary metastatic sites in breast cancer.
• The tumor microenvironment in metastatic lymph nodes (mLNs) and immune cell interactions are poorly understood.
• Regulatory B cells (Bregs) are implicated in immune modulation.

Purpose of the Study:

• To investigate the role of CD24hiCD27+ Bregs in mLNs of breast cancer patients.
• To explore the effect of Bregs on breast cancer cell drug resistance.
• To evaluate therapeutic strategies targeting Breg-tumor cell interactions.

Main Methods:

• Analysis of mLN samples from breast cancer patients post-neoadjuvant therapy (NAT).
• Multicolor immunofluorescence staining for spatial analysis of CD24hiCD27+ Bregs.
• In vitro drug resistance assays and mouse models of mLNs.
• Evaluation of PD-L1 blockade and chemoimmunotherapy.

Main Results:

• A close spatial correlation exists between activated CD24hiCD27+ Bregs and residual tumor cells in mLNs after NAT.
• CD24hiCD27+ Bregs enhance multidrug resistance and stem-like features in breast cancer cells via IL6 and TNFα secretion.
• A positive feedback loop is established through CD40L and PD-L1 signaling between breast cancer cells and Bregs.
• PD-L1 blockade reduces Breg-induced drug resistance, and anti-PD-L1 combined with chemotherapy improves tumor regression in mLNs.

Conclusions:

• CD24hiCD27+ Bregs play a critical role in promoting breast cancer drug resistance within mLNs.
• Targeting the interaction between Bregs and breast cancer cells offers a promising therapeutic avenue.
• Combination chemoimmunotherapy involving PD-L1 blockade represents an improved strategy for breast cancer patients with lymph node metastasis.