The transcription factor ZNF148 promotes the malignant transformation of dendritic cells after cross-talk with glioma stem cells by upregulating PTX3

Abstract

Abstract The recent development of dendritic cell (DC)-based immunotherapy has resulted in advances in glioblastoma multiforme (GBM) treatment. However, the cell fate of DCs in the GBM microenvironment, especially in microenvironments in which glioma stem cell (GSC)-mediated remodeling has resulted in highly immuno-suppressive conditions, has not yet been fully investigated. The current study observed direct and active mutual interactions between GSCs and primary cultured DCs in a dual-color tracing model. Highly proliferative DCs could be monoclonal and continuously passaged, and these cells exhibited acquired tumorigenicity in vivo, indicating their malignant transformation. Transformed DCs (t-DCs) still expressed DC-specific surface markers, namely, CD80 and CD11c, and immune-related costimulatory molecules, namely, CD80, CD86, CD40, and ICAM-1. However, the expression levels of these molecules in t-DCs decreased moderately compared to those in naive DCs. Mechanistic studies revealed the upregulation of the proliferation-related gene pentraxin 3 (PTX3) in t-DCs. Stable overexpression of PTX3 further promoted the proliferation and migration of t-DCs in vitro, decreased the expression of costimulatory molecules, and increased the tumorigenicity of t-DCs in vivo. Bioinformatics prediction, qRT‒PCR verification, and luciferase reporter gene analysis indicated that the transcription factor zinc finger protein 148 (ZNF148) directly bound to the PTX3 promoter region and enhanced PTX3 expression. Downregulation of ZNF148 significantly decreased PTX3 expression and reduced the proliferation and migration of t-DCs. Overexpression of ZNF148 significantly increased PTX3 expression and promoted the proliferation and migration of t-DCs, achieving the same biological effects as PTX3 overexpression in t-DCs. Simultaneously, downregulation of ZNF148 partially reversed the effect of PTX3 overexpression in t-DCs. In conclusion, the ZNF148/PTX3 axis played an important role in regulating the malignant transformation of DCs after cross-talk with GSCs, and this axis may serve as a new target for sensitizing GBM to DC-based immunotherapy.