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Supplementary Figure S4 from CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer

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posted on 2023-12-15, 08:42 authored by Huanhuan Huang, Yao Yao, Lesang Shen, Jingxin Jiang, Ting Zhang, Jia Xiong, Jiaxin Li, Shanshan Sun, Siwei Zheng, Fang Jia, Jun Zhou, Xiuyan Yu, Wuzhen Chen, Jun Shen, Wenjie Xia, Xuan Shao, Qingqing Wang, Jian Huang, Chao Ni

Fig. S4. CD24hiCD27+ Breg-induced drug resistance in BC is independent of small molecule substances.

Funding

Natural Science Foundation of Zhejiang Province (ZJNSF)

National Natural Science Foundation of China (NSFC)

the leading innovative and Entrepreneur Team Introduction Program of Zhejiang

Zhejiang Basic Public Welfare Research Project

National Key Research and Development Program of China (NKPs)

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ARTICLE ABSTRACT

Axillary lymph nodes (LN) are the primary and dominant metastatic sites in breast cancer. However, the interaction between tumor cells and immune cells within metastatic LNs (mLN) remains poorly understood. In our study, we explored the effect of CD24hiCD27+ regulatory B cells (Breg) within mLNs on orchestrating drug resistance of breast cancer cells. We collected mLN samples from patients with breast cancer who had received standard neoadjuvant therapy (NAT) and analyzed the spatial features of CD24hiCD27+ Bregs through multicolor immunofluorescence staining. The effect of CD24hiCD27+ Bregs on drug resistance of breast cancer cells was evaluated via in vitro experiments. A mouse model with mLNs was used to evaluate the strategies with blocking the interactions between Bregs and breast cancer for improving tumor regression within mLNs. In patients with breast cancer who had received NAT, there is a close spatial correlation between activated CD24hiCD27+ Bregs and residual tumor cells within mLNs. Mechanistically, CD24hiCD27+ Bregs greatly enhance the acquisition of multidrug resistance and stem-like features of breast cancer cells by secreting IL6 and TNFα. More importantly, breast cancer cells further promote the activation of CD24hiCD27+ Bregs via CD40L-dependent and PD-L1–dependent proximal signals, forming a positive feedback pattern. PD-L1 blockade significantly attenuates the drug resistance of breast cancer cells induced by CD24hiCD27+ Bregs, and addition of anti-PD-L1 antibody to chemotherapy improves tumor cell remission in mLNs. Our study reveals the pivotal role of CD24hiCD27+ Bregs in promoting drug resistance by interacting with breast cancer cells in mLNs, providing novel evidence for an improved strategy of chemoimmunotherapy combination for patients with breast cancer with mLNs.

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