Journal Article

The interaction between the soluble programmed death ligand-1 (sPD-L1) and PD-1+ regulator B cells mediates immunosuppression in triple-negative breast cancer

Wan, Yuqiu, Zhan, Shenghua, Xie, Fang, Yang, Yang, Lan, Jing, Wang, Zhangyu, PuYang, Longxiang, Wang, Sining, Du, Huan, Li, Xuejiao, Liu, Wenting, Qu, Qiuxia, Wang, Qin

2022

Overview

Accumulating evidence suggests that regulatory B cells (Bregs) play important roles in inhibiting the immune response in tumors. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important molecules that maintain the balance of the immune response and immune tolerance. This study aims to evaluate the soluble form of PD-L1 and its function in inducing the differentiation of B lymphocytes, investigate the relationship between soluble PD-L1 (sPD-L1) and B-cell subsets, and explore the antitumor activity of T lymphocytes after PD-L1 blockade in coculture systems. In an effort to explore the role of sPD-L1 in human breast cancer etiology, we examined the levels of sPD-L1 and interleukin-10 (IL-10) in the serum of breast tumor patients and the proportions of B cells, PD-1 + B cells, Bregs, and PD-1 + Bregs in the peripheral blood of patients with breast tumors and assessed their relationship among sPD-L1, IL-10, and B-cell subsets. The levels of sPD-L1 and IL-10 in serum were found to be significantly higher in invasive breast cancer (IBCa) patients than in breast fibroadenoma (FIBma) patients. Meanwhile, the proportions and absolute numbers of Bregs and PD-1 + Bregs in the peripheral blood of IBCa patients were significantly higher than those of FIBma patients. Notably, they were the highest in triple-negative breast cancer (TNBC) among other subtypes of IBCa. Positive correlations of sPD-L1 and IL-10, IL-10 and PD-1 + Bregs, and also sPD-L1 and PD-1 + Bregs were observed in IBCa. We further demonstrated that sPD-L1 could induce Breg differentiation, IL-10 secretion, and IL-10 mRNA expression in a dose-dependent manner in vitro . Finally, the induction of regulatory T cells (T regs ) by Bregs was further shown to suppress the antitumor response and that PD-L1 blockade therapies could promote the apoptosis of tumor cells. Together, these results indicated that sPD-L1 could mediate the differentiation of Bregs, expand CD4 + T regs and weaken the antitumor activity of CD4 + T cells. PD-L1/PD-1 blockade therapies might be a powerful therapeutic strategy for IBCa patients, particularly for TNBC patients with high level of PD-1 + Bregs.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Antitumor activity / Apoptosis / Breast cancer / Cancer therapies / CD4 antigen / Cells / Cloning / Death / Fibroadenoma / Flow cytometry / Gene expression / Immunological tolerance / Immunology / Immunoregulation / Immunosuppression / Immunotherapy / Interleukin 10 / Ligands / Lymphatic system / Lymphocytes / Lymphocytes B / Lymphocytes T / Metastasis / Monoclonal antibodies / PD-1 protein / PD-1+ regulator B cells / PD-L1 protein / Peripheral blood / regulator T cell / sPD-L1 / the triple-negative breast cancer / Tumor cells / Tumors