Neutrophil-Mediated Alteration of CXCL1/IL-8/AR Signaling Promotes Prostate Cancer Cell Proliferation

The role of immune cells, particularly neutrophils, in prostate cancer (PCa) progression remains poorly understood. In this study, we investigated the impact of neutrophils on PCa progression using an in vitro co-culture migration system. Our findings revealed that PCa cells recruited a higher number of neutrophils compared to normal prostate epithelial cells. Importantly, the recruitment of neutrophils to PCa cells resulted in increased proliferation of PCa cells. Further mechanistic investigations unveiled that co-culturing PCa cells with neutrophils led to increased secretion of the chemokine CXCL1. This, in turn, stimulated the production of the cytokine IL-8 from neutrophils. The enhanced CXCL1/IL-8 signaling axis subsequently amplified androgen receptor (AR) signaling in PCa cells, promoting their proliferation. Interrupting this pathway using IL-8 neutralizing antibodies or AR knockdown reversed the neutrophil-induced PCa cell proliferation. Our findings were validated in a mouse model and supported by clinical sample analysis. Collectively, our study highlights the potential therapeutic implications of targeting the newly identified signaling cascade involving infiltrating neutrophils within the PCa microenvironment. By understanding and modulating this pathway, we may develop novel strategies to suppress the progression of PCa.