Publication Date
3-1-2023
Journal
The Journal for ImmunoTherapy of Cancer
DOI
10.1136/jitc-2022-005478
PMID
36882225
PMCID
PMC10008329
PubMedCentral® Posted Date
3-7-2023
PubMedCentral® Full Text Version
Post-print
Abstract
BACKGROUND: Tumor progression and resistance to therapy in children with neuroblastoma (NB), a common childhood cancer, are often associated with infiltration of monocytes and macrophages that produce inflammatory cytokines. However, the mechanism by which tumor-supportive inflammation is initiated and propagated remains unknown. Here, we describe a novel protumorigenic circuit between NB cells and monocytes that is triggered and sustained by tumor necrosis factor alpha (TNF-α).
METHODS: We used NB knockouts (KOs) of TNF-α and
RESULTS: We found that NB expression of TNFR2 and monocyte membrane-bound tumor necrosis factor alpha is required for monocyte activation and interleukin (IL)-6 production, while NB TNFR1 and monocyte soluble TNF-α are required for NB nuclear factor kappa B subunit 1 (NF-κB) activation. Treatment of NB-monocyte cocultures with clinical-grade etanercept completely abrogated release of IL-6, granulocyte colony-stimulating factor (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 TNF-α signaling in patients with NB that relapsed.
CONCLUSIONS: We have described a novel mechanism of tumor-promoting inflammation in NB that is strongly associated with patient outcome and could be targeted with therapy.
Keywords
Animals, Humans, Mice, Carcinogenesis, Etanercept, Mice, Inbred NOD, Mice, SCID, Monocytes, Neuroblastoma, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Tumor Necrosis Factor-alpha
Published Open-Access
yes
Recommended Citation
Tomolonis, Julie A; Xu, Xin; Dholakia, Kshiti H; et al., "Interaction Between Tumor Cell TNFR2 and Monocyte Membrane-Bound TNF-α Triggers Tumorigenic Inflammation in Neuroblastoma" (2023). Faculty, Staff and Students Publications. 6321.
https://digitalcommons.library.tmc.edu/baylor_docs/6321