Tissue-resident CXCR4+ macrophage as a poor prognosis signature promotes pancreatic ductal adenocarcinoma progression

Macrophage is an essential part of the tumor immune microenvironment of pancreatic ductal adenocarcinoma. In our study, we explored the CXCR4(+) macrophages subset on its prognosis value, immune profile and distinct function in pancreatic cancer progression. Specimens from 102 postoperative pancreatic patients were analyzed by flow cytometry or immune-fluorescence, and the prognostic value of CXCR4(+) macrophages infiltration was further determined by Cox regression. In silico analysis on TCGA, ICGC database and single-cell sequencing of pancreatic ductal adenocarcinoma further validated our findings. We found that high CXCR4(+) macrophages infiltration was associated with poor overall survival (P < .01) and disease-free survival (P < .05) as an independent factor. CXCR4(+) macrophages exhibited an M2 protumor phenotype with high expression of CD206. The function of CXCR4(+) macrophages was further analyzed in the murine orthotopic PDAC model with its tumor promotion effect and inhibition of CD8(+) T cells. Mechanistic and RNA-seq analysis showed that CXCR4(+) macrophages participated in extracellular matrix remodeling procedures and especially secreted SPARC through CXCR4/PI3K/Akt pathway promoting tumor proliferation and migration. Our study reveals that CXCR4(+) macrophages infiltration is an indicator of poor prognosis of PDAC and targeting these cells was potentially crucial in immunotherapy of PDAC.