Interaction between stromal cells and tumor cells promotes GCB-DLBCL cell survival via the CD40/RANK-KDM6B-NF-κB axis.

The stromal cells as the main component of the tumor microenvironment in germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) probably is accountable for therapy resistance and relapse. To investigate the interaction between tumor cells and stromal cells, we established GCB-DLBCL patient-derived xenograft models to isolate primary tumor cells and coculture them with stromal cells. Additionally, we presented GCB-DLBCL cases with histopathologic confirmation and analyzed the online databases to explore the underlying mechanisms. We demonstrated that CD40 ligand (CD40L) expressed on stromal cells activated the CD40 pathway in GCB-DLBCL tumor cells, protecting tumor cells from apoptosis and up-regulating RANK ligand (RANKL). The RANKL expressed on tumor cells enhanced the expression of CD40L and BAFF in stromal cells, which in turn promoted tumor cells survival through activating NF-κB signaling. Significantly, the activation of CD40 pathway up-regulated KDM6B, a lysine-specific demethylase, and KDM6B further enhanced the transcription activity of NF-κB signaling, which has not been reported in B cells. Here, we provided compelling evidence that the interaction between stromal cells and tumor cells functions as a bona fide anti-apoptotic factor in GCB-DLBCL. This interaction mainly involves the CD40/RANK-KDM6B-NF-κB axis, which represents a promising therapeutic target for GCB-DLBCL.