Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Department of Forensic Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Pathol Res Pract. 2024 Aug;260:155458. doi: 10.1016/j.prp.2024.155458. Epub 2024 Jul 9.
M2 macrophages are known to play a significant role in the progression of triple-negative breast cancer (TNBC) by creating an immunosuppressive microenvironment. The aim of this study is to investigate the impact of M2 macrophages on TNBC and their correlation with programmed death-ligand 1 (PD-L1) expression.
We employed a co-culture system to analyze the role of the mutual regulation of M2 macrophages and TNBC cells. Employing a multifaceted approach, including bioinformatics analysis, Western blotting, flow cytometry analysis, ELISA, qRT-PCR, lentivirus infection, mouse models, and IHC, we aimed to elucidate the influence and mechanism of M2 macrophages on PD-L1 expression.
The results showed a substantial infiltration of M2 macrophages in TNBC tissue, which demonstrated a positive correlation with PD-L1 expression. CXCL1 exhibited abnormally high expression in M2 macrophages and enhanced the expression of PD-L1 in TNBC cells. Notably, silencing CXCL1 or its receptor CXCR2 inhibited M2 macrophages-induced expression of PD-L1. Mechanistically, CXCL1 derived from M2 macrophages binding to CXCR2 activated the PI3K/AKT/NF-κB signaling pathway, resulting in increased PD-L1 expression in TNBC.
Broadly speaking, these results provide evidence for the immunosuppressive role of M2 macrophages and CXCL1 in TNBC cells, indicating their potential as therapeutic biomarkers.
M2 巨噬细胞通过创造免疫抑制微环境，在三阴性乳腺癌（TNBC）的进展中起着重要作用。本研究旨在探讨 M2 巨噬细胞对 TNBC 的影响及其与程序性死亡配体 1（PD-L1）表达的相关性。
我们采用共培养系统来分析 M2 巨噬细胞和 TNBC 细胞相互调节的作用。我们采用包括生物信息学分析、Western blot 分析、流式细胞术分析、ELISA、qRT-PCR、慢病毒感染、小鼠模型和免疫组化在内的多种方法，旨在阐明 M2 巨噬细胞对 PD-L1 表达的影响及其机制。
结果显示，TNBC 组织中 M2 巨噬细胞大量浸润，与 PD-L1 表达呈正相关。M2 巨噬细胞中 CXCL1 表达异常升高，并增强 TNBC 细胞中 PD-L1 的表达。值得注意的是，沉默 CXCL1 或其受体 CXCR2 抑制了 M2 巨噬细胞诱导的 PD-L1 表达。机制上，M2 巨噬细胞来源的 CXCL1 与 CXCR2 结合，激活了 PI3K/AKT/NF-κB 信号通路，导致 TNBC 中 PD-L1 的表达增加。
总的来说，这些结果为 M2 巨噬细胞和 CXCL1 在 TNBC 细胞中的免疫抑制作用提供了证据，表明它们可能作为治疗的生物标志物。
