GSE202370
Interaction between stromal cells and GCB-DLBCL cells promotes the tumor cell survival through CD40-KDM6B-NF-?B axis
Germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is one of the most common subtypes of B-cell non-Hodgkin lymphoma. The tumor microenvironment (TME) is responsible for therapy resistance and relapse in GCB-DLBCL, while most studies have focused on targeting tumor cells instead of the TME. Stromal cells are the main component of the TME in GCB-DLBCL. How stromal cells interact with GCB-DLBCL tumor cells and protect GCB-DLBCL from cell death remain elusive. Here we reported that a CD40/RANK pathway-mediated positive feedback loop mediated the interaction of stromal cells and GCB-DLBCL to enhance the survival of GCB-DLBCL tumor cells. The viability of primary GCB-DLBCL patient-derived xenograft tumor cells was increased when they were cocultured with different tissue-derived stromal cells. We demonstrated that stromal cells promoted tumor cell survival not only through excreted cytokines but also depending more on direct contact. Furthermore, CD40 ligand (CD40L) expressed on stromal cells activated CD40 signaling in tumor cells, protecting tumor cells from apoptosis and upregulating RANK ligand (RANKL). RANK activation by RANKL in tumor cells enhanced the expression of CD40L and BAFF in stromal cells, both of which in turn promoted tumor cell survival through activating canonical and noncanonical NF-?B signaling. In addition, CD40 activation upregulated the expression of KDM6B, and KDM6B further mediated the activation of canonical and noncanonical NF-?B signaling, the downstream signaling pathways of the CD40 activation, all leading to tumor cell survival. These results further suggest that CD40-KDM6B-NF-?B axis serve as a potential target for GCB-DLBCL therapy. Overall design: Comparative gene expression profiling analysis of RNA-seq data for sorted mono-cultured GCB-DLBCL PDX tumor cells and co-cultured GCB-DLBCL PDX tumor cells.