Myeloid-derived suppressor cells regulate the immunosuppressive functions of PD-1−PD-L1+ Bregs through PD-L1/PI3K/AKT/NF-κB axis in breast cancer

• Main Authors: Min Liu, Feng Wei, Jian Wang, Wenwen Yu, Meng Shen, Ting Liu, Dong Zhang, Yang Wang, Xiubao Ren, Qian Sun
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-05-01
• Series: Cell Death and Disease
• Online Access: https://doi.org/10.1038/s41419-021-03745-1

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that are closely related to tumor immune escape, but the mechanism by which MDSCs regulate B cells has not been elucidated. Our previous studies revealed that breast cancer-derived MDSCs could induce a group of PD-1−PD-L1+ Bregs with immunosuppressive functions. Here, we reported that blocking PD-1/PD-L1 interaction between MDSCs and B cells could reverse the immunosuppressive functions of PD-1−PD-L1+ Bregs. The activation of PI3K/AKT/NF-κB signaling pathway is essential for PD-1−PD-L1+ Bregs to exert immunosuppressive effects. MDSCs activated the PI3K/AKT/NF-κB pathway in B cells via the PD-1/PD-L1 axis. Furthermore, inhibition of PD-1/PD-L1 or PI3K/AKT signaling suppressed both tumor growth and the immunosuppressive functions of PD-1−PD-L1+ Bregs. Dual suppression of PD-1/PD-L1 and PI3K/AKT exerted better antitumor effect. Finally, MDSCs and PD-1−PD-L1+ Bregs were colocalized in breast cancer tissues and PD-1−PD-L1+ Bregs were positively correlated with poor prognosis. Thus, MDSC-educated PD-1−PD-L1+ Bregs and their regulatory mechanisms could contribute to the immunosuppressive tumor microenvironment. Our study proposes a novel mechanism for MDSC-mediated regulation of B cell immunity, which might shed new light on tumor immunotherapy.+