CD47 signaling is essential in modulating immune responses within the tumor microenvironment. This study investigates how IL-8/CXCR2 signaling affects CD47 expression in prostate cancer cells and its impact on macrophage infiltration, providing new insights for potential therapeutic approach.

Prostate cancer tissue samples and cell lines were used to study IL-8/CXCR2 induced changes in CD47 expression. Macrophage infiltration was analyzed via flow cytometry and IHC. Phagocytosis and transwell assays evaluated macrophage responses, while Peripheral Blood Mononuclear Cells (PBMCs) were differentiated into macrophages for co-culture experiments. Protein expression and signaling mechanisms were examined using western blot, PCR, and luciferase assays. Metabolomic profiling via Liquid Chromatography-Mass Spectrometry (LC-MS) assessed fatty acid metabolism. Animal models were used to study tumor growth and macrophage activity following CXCR2 or CD47 pathway inhibition.

IL-8/CXCR2 pathway significantly upregulated CD47 expression in tumor cells, attenuated their susceptibility to macrophage-mediated phagocytosis. Tumor-bearing mice treated with the CXCR2 inhibitor Navarixin or CD47 inhibitor CC-90002 exhibited a significant reduction in tumor growth compared to control groups. Additionally, blockade of these pathways restored the phagocytic activity of tumor-associated macrophages (TAM). Flow cytometry analysis of tumor tissues revealed an increased presence of TAM (CD11b+F4/80+) and an enhanced ability of these macrophages to phagocytose tumor cells following CXCR2 and CD47 inhibition.

Collectively, these results suggest that blocking the IL-8/CXCR2 and CD47 pathways can reverse immune evasion mechanisms and restore the anti-tumor activity of macrophages.