2. Academic Validation
  3. CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer

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

  • Clin Cancer Res. 2023 Dec 15;29(24):5227-5243. doi: 10.1158/1078-0432.CCR-23-1759.
Huanhuan Huang # 1 2 3 4,  Yao Yao # 1 2 3,  Lesang Shen # 1 2 3,  Jingxin Jiang # 1 2 3,  Ting Zhang 2 3 5,  Jia Xiong 6 7,  Jiaxin Li 1 2 3,  Shanshan Sun 1 2 3,  Siwei Zheng 1 2 3,  Fang Jia 1 2 3,  Jun Zhou 8,  Xiuyan Yu 1 2 3,  Wuzhen Chen 1 2 3,  Jun Shen 9,  Wenjie Xia 10,  Xuan Shao 1 2 3,  Qingqing Wang 6 7,  Jian Huang 1 2 3,  Chao Ni 1 2 3
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 2 Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 3 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 4 Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, P.R. China.
  • 5 Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 6 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P.R. China.
  • 7 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, P.R. China.
  • 8 Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 9 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 10 Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, P.R. China.
  • # Contributed equally.
PMID: 37831062 DOI: 10.1158/1078-0432.CCR-23-1759
Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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.

Figures
Products