Identification of M2 macrophage-related genes for establishing a prognostic model in pancreatic cancer: FCGR3A as key gene.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a rich and complex tumor immune microenvironment (TIME). M2 macrophages are among the most extensively infiltrated immune cells in the TIME and are necessary for the growth and migration of cancers. However, the mechanisms and targets mediating M2 macrophage infiltration in pancreatic cancer remain elusive.

Methods: The M2 macrophage infiltration score of patients was assessed using the xCell algorithm. Using weighted gene co-expression network analysis (WGCNA), module genes associated with M2 macrophages were identified, and a predictive model was designed. The variations in immunological cell patterns, cancer mutations, and enrichment pathways between the cohorts with the high- and low-risk were examined. Additionally, the expression of FCGR3A and RNASE2, as well as their association with M2 macrophages were evaluated using the HPA, TNMplot, and GEPIA2 databases and verified by tissue immunofluorescence staining. Moreover, in vitro cell experiments were conducted, where FCGR3A was knocked down in pancreatic cancer cells using siRNA to analyze its effects on M2 macrophage infiltration, tumor proliferation, and metastasis.

Results: The prognosis of patients in high-risk and low-risk groups was successfully distinguished using a prognostic risk score model of M2 macrophage-related genes (p = 0.024). Between the high- and low-risk cohorts, there have been notable variations in immune cell infiltration patterns, tumor mutations, and biological functions. The risk score was linked to the manifestation of prevalent immunological checkpoints, immunological scores, and stroma values (all p < 0.05). In vitro experiments and tissue immunofluorescence staining revealed that FCGR3A can promote the infiltration or polarization of M2 macrophages and enhance tumor proliferation and migration.

Conclusions: In this study, an M2 macrophage-related pancreatic cancer risk score model was established, and found that FCGR3A was correlated with tumor formation, metastasis, and M2 macrophage infiltration.