M2 macrophages promote PD-L1 expression in triple-negative breast cancer via secreting CXCL1

Abstract M2-like tumor-associated macrophages (M2-like TAMs) 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 association with PD-L1 expression. The results showed a high infiltration of M2 macrophages in TNBC tissue, which correlated positively with PD-L1 expression. Upon analyzing the expression of various cytokines in macrophages, it was found that CXCL1 showed abnormally high expression in M2 macrophages. CXCL1 specifically increased the expression of PD-L1 in TNBC cells. Notably, when CXCL1 or its receptor CXCR2 was silenced, the facilitation of PD-L1 expression by M2 macrophages was inhibited. Mechanistically, CXCL1 derived from M2 macrophages binding CXCR2 activated the PI3K/AKT/NF-κB signaling pathway, generating increased PD-L1 expression in TNBC. To validate these findings, xenograft tumor models were employed, demonstrating a positive correlation between CXCR2, phospho-AKT, phospho-p65 and PD-L1 expression with treatment with M2 macrophages in the xenograft tumor tissue. Broadly speaking, these results provide evidence for the immunosuppressive role of M2 macrophages and CXCL1 in tumor cells, suggesting their potential as therapeutic biomarkers for TNBC.