{"doi":"10.1136/jitc-2022-005478","title":"Interaction between tumor cell TNFR2 and monocyte membrane-bound TNF-α triggers tumorigenic inflammation in neuroblastoma","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: mRNA (TNFR2) and TNF-α protease inbitor (TAPI), a drug that modulates TNF-α isoform expression, to assess the role of each component in monocyte-associated protumorigenic inflammation. Additionally, we employed NB-monocyte cocultures and treated these with clinical-grade etanercept, an Fc-TNFR2 fusion protein, to neutralize signaling by both membrane-bound (m) and soluble (s)TNF-α isoforms. Further, we treated NOD/SCID/IL2Rγ(null) mice carrying subcutaneous NB/human monocyte xenografts with etanercept and evaluated the impact on tumor growth and angiogenesis. Gene set enrichment analysis (GSEA) was used to determine whether TNF-α signaling correlates with clinical outcomes in patients with NB. 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.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":338133,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":890390,"name":"Xin Xu","orcid":"0000-0002-9485-8782","position":1,"is_corresponding":false},{"id":930939,"name":"Kshiti H. Dholakia","orcid":"0000-0002-5807-0058","position":2,"is_corresponding":false},{"id":331569,"name":"Chunchao Zhang","orcid":"0000-0001-5615-0401","position":3,"is_corresponding":false},{"id":238431,"name":"Linjie Guo","orcid":"0000-0002-3163-8176","position":4,"is_corresponding":false},{"id":238432,"name":"Amy N. Courtney","orcid":"0000-0001-7013-3042","position":5,"is_corresponding":false},{"id":1070509,"name":"Siyue Wang","orcid":"0000-0003-2952-5882","position":6,"is_corresponding":false},{"id":238433,"name":"Julien Balzeau","orcid":"0000-0003-4717-2638","position":7,"is_corresponding":false},{"id":890389,"name":"Gabriel A. Barragán","orcid":"0000-0002-9405-109X","position":8,"is_corresponding":false},{"id":854388,"name":"Gengwen Tian","orcid":"0000-0002-4339-6266","position":9,"is_corresponding":false},{"id":890396,"name":"Erica J. Di Pierro","orcid":"0000-0003-3185-7376","position":10,"is_corresponding":false},{"id":238437,"name":"Leonid S. Metelitsa","orcid":"0000-0002-9639-6630","position":11,"is_corresponding":false},{"id":1070508,"name":"Julie Tomolonis","orcid":"0000-0002-6012-3948","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:10:35.973121Z","pmid":"36882225","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}