Fc gamma receptor IIb in tumor-associated macrophages and dendritic cells drives poor prognosis of recurrent glioblastoma through immune-associated signaling pathways

Background: Among central nervous system tumors, glioblastoma (GBM) is considered to be the most destructive malignancy. Recurrence is one of the most fatal aspects of GBM. However, the driver molecules that trigger GBM recurrence are currently unclear.Methods: The mRNA expression data and clinical information of GBM and normal tissues were collected from the Chinese Glioma Genome Atlas The Cancer Genome Atlas (TCGA), and REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) cohorts. The DESeq2 R package was used to identify the differentially expressed genes between primary and recurrent GBM. ClueGO, Kyoto Encyclopedia of Genes and Genomes (KEGG), Biological Process in Gene ontology (GO-BP), and the Protein ANalysis THrough Evolutionary Relationships (PANTHER) pathway analyses were performed to explore the enriched signaling pathways in upregulated DEGs in recurrent GBM. A gene list that contained potential oncogenes that showed a significant negative correlation with patient survival from The Cancer Genome Atlas was used to further screen driver candidates for recurrent GBM. Univariate Cox proportional hazards regression analyses were used to investigate the risk score for the mRNA expression of the candidates. Single-cell RNA sequencing (scRNA-Seq) analyses were used to determine the cell type-specific distribution of Fc gamma receptor II b (Fc gamma RIIb) in GBM. Immunohistochemistry (IHC) was used to confirm the Fc gamma RIIb-positive cell populations in primary and paired recurrent GBM.Results: Through DEG analysis and overlap analysis, a total of 10 genes that are upregulated in recurrent GBM were screened. Using validation databases, Fc gamma RIIb was identified from the 10 candidates that may serve as a driver for recurrent GBM. FCGR2B expression, not mutation, further showed a highly negative correlation with the poor prognosis of patients with recurrent GBM. Furthermore, scRNA-Seq analyses revealed that tumor-associated macrophage- and dendritic cell-specific FCGR2B was expressed. Moreover, Fc gamma RIIb also showed a strong positive correlation coefficient with major immune-associated signaling pathways. In clinical specimens, Fc gamma RIIb-positive cell populations were higher in recurrent GBM than in primary GBM.Conclusion: This study provides novel insights into the role of Fc gamma RIIb in recurrent GBM and a promising strategy for treatment as an immune therapeutic target.

Automated summary

This study identified Fc gamma RIIb as a potential driver for recurrent GBM based on gene expression analysis. Further investigations revealed a highly negative correlation between FCGR2B expression and poor prognosis in patients with recurrent GBM. The study also found that Fc gamma RIIb was strongly associated with immune-related signaling pathways and expressed in tumor-associated macrophages and dendritic cells. These findings provide novel insights into the role of Fc gamma RIIb in recurrent GBM and suggest it as a promising immune therapeutic target.