Neutrophil-mediated alteration of CXCL1/IL-8/AR signaling promotes prostate cancer cell proliferation

This is the authors' abstract. We don't add key points for this paper.

The role of immune cells, particularly neutrophils, in the 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 assay. Our findings revealed that PCa cells recruited more neutrophils than normal prostate epithelial cells. Importantly, the recruitment of neutrophils to PCa cells led to increased PCa cell proliferation. Further mechanistic investigations revealed that co-culture of PCa cells with neutrophils led to increased secretion of the chemokine CXCL1. This, in turn, stimulated neutrophils to produce the cytokine IL-8. The enhanced CXCL1/IL-8 signaling axis subsequently amplified androgen receptor (AR) signaling in PCa cells, thereby promoting their proliferation. Disruption of this pathway via IL-8 neutralizing antibodies or AR knockdown reversed the neutrophil-induced PCa cell proliferation. These findings were validated in a mouse model and further supported by clinical sample analysis. Collectively, our study highlights the therapeutic potential of targeting the newly identified signaling cascade involving infiltrating neutrophils within the PCa microenvironment. Understanding and modulating this pathway may offer novel strategies to suppress PCa progression. • Neutrophil infiltration promoted PCa cell proliferation through AR signaling. • CXCL1 secretion by PCa cells triggered IL-8 release from neutrophils. • IL-8/AR axis enhanced PCa cell proliferation, reversible with IL-8 neutralization. • In vivo and clinical analysis confirmed neutrophil-driven PCa progression.