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

• Published in: Cell death & disease 2021-05, Vol.12 (5), p.465-465, Article 465
• Main Authors: Liu, Min, Wei, Feng, Wang, Jian, Yu, Wenwen, Shen, Meng, Liu, Ting, Zhang, Dong, Wang, Yang, Ren, Xiubao, Sun, Qian
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/109; 13/31; 13/51; 13/89; 13/95; 14/28; 64/60; 692/699/67/1347; 692/699/67/327; AKT protein; Antibodies; Antitumor activity; Biochemistry; Biomedical and Life Sciences; Breast cancer; Cell Biology; Cell Culture; Immunology; Immunotherapy; Life Sciences; Lymphocytes B; Myeloid cells; NF-κB protein; PD-1 protein; PD-L1 protein; Signal transduction; Suppressor cells; Tumor microenvironment
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03745-1

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. +