High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach.

Background: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM.

Methods: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/β-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression.

Results: In analyses of 31 genes related to Wnt/β-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression.

Conclusions: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.