Interaction between tumor cell TNFR2 and monocyte membrane-bound TNFa triggers tumorigenic inflammation in neuroblastoma

We found that NB expression of TNFR2 and monocyte mTNFa are required for monocyte activation and IL-6 production, while NB TNFR1 and monocyte sTNFa are required for NB NF-?B activation. Treatment of NB-monocyte co-cultures with clinical-grade etanercept completely abrogated release of IL-6, G-CSF, IL-1a, and IL-1ß and eliminated monocyte-induced enhancement of NB cell proliferation in vitro. Furthermore, etanercept treatment inhibited tumor growth, ablated tumor angiogenesis, and suppressed oncogenic signaling in mice with subcutaneous NB/human monocyte xenografts. Finally, GSEA revealed significant enrichment for TNFa signaling in NB patients that relapsed. Overall design: Comparative gene expression profiling analysis of RNA-seq data on etanercept-treated and control tumors