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

We found that NB expression of TNFR2 and monocyte mTNFα are required for monocyte activation and IL-6 production, while NB TNFR1 and monocyte sTNFα are required for NB NF-κB activation. Treatment of NB-monocyte co-cultures with clinical-grade etanercept completely abrogated release of IL-6, G-CSF, IL-1α, and IL-1β 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 TNFα signaling in NB patients that relapsed. Comparative gene expression profiling analysis of RNA-seq data on etanercept-treated and control tumors