Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Cell Death Dis. 2021 May 9;12(5):465. 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-1PD-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-1PD-L1 Bregs. The activation of PI3K/AKT/NF-κB signaling pathway is essential for PD-1PD-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-1PD-L1 Bregs. Dual suppression of PD-1/PD-L1 and PI3K/AKT exerted better antitumor effect. Finally, MDSCs and PD-1PD-L1 Bregs were colocalized in breast cancer tissues and PD-1PD-L1 Bregs were positively correlated with poor prognosis. Thus, MDSC-educated PD-1PD-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.
髓系来源的抑制性细胞（MDSCs）是一组与肿瘤免疫逃逸密切相关的异质性髓系细胞，但 MDSCs 调节 B 细胞的机制尚未阐明。我们之前的研究表明，乳腺癌来源的 MDSCs 可以诱导一群具有免疫抑制功能的 PD-1PD-L1B 调节性 B 细胞（Bregs）。在这里，我们报道了阻断 MDSCs 和 B 细胞之间的 PD-1/PD-L1 相互作用可以逆转 PD-1PD-L1Bregs 的免疫抑制功能。PI3K/AKT/NF-κB 信号通路的激活对于 PD-1PD-L1Bregs 发挥免疫抑制作用是必不可少的。MDSCs 通过 PD-1/PD-L1 轴在 B 细胞中激活 PI3K/AKT/NF-κB 通路。此外，抑制 PD-1/PD-L1 或 PI3K/AKT 信号通路抑制了肿瘤生长和 PD-1PD-L1Bregs 的免疫抑制功能。PD-1/PD-L1 和 PI3K/AKT 的双重抑制发挥了更好的抗肿瘤作用。最后，MDSCs 和 PD-1PD-L1Bregs 在乳腺癌组织中聚集，并且 PD-1PD-L1Bregs 与不良预后呈正相关。因此，MDSC 诱导的 PD-1PD-L1Bregs 及其调节机制可能有助于免疫抑制性肿瘤微环境。我们的研究提出了 MDSC 介导的 B 细胞免疫调节的新机制，这可能为肿瘤免疫治疗提供新的思路。
