{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:56:41Z","timestamp":1792195001338,"version":"4.4.0"},"reference-count":52,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T00:00:00Z","timestamp":1678147200000},"content-version":"unspecified","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001234","name":"Robert and Janice McNair Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100001234","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 CA116548"],"award-info":[{"award-number":["RO1 CA116548"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 CA262250"],"award-info":[{"award-number":["RO1 CA262250"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RP160283"],"award-info":[{"award-number":["RP160283"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,1,23]]},"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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-\u03b1).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We used NB knockouts (KOs) of TNF-\u03b1 and <jats:italic>TNFRSF1A<\/jats:italic> mRNA (TNFR1)\/<jats:italic>TNFRSF1B<\/jats:italic> mRNA (TNFR2) and TNF-\u03b1 protease inbitor (TAPI), a drug that modulates TNF-\u03b1 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-\u03b1 isoforms. Further, we treated NOD\/SCID\/IL2R\u03b3(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-\u03b1 signaling correlates with clinical outcomes in patients with NB.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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-\u03b1 are required for NB nuclear factor kappa B subunit 1 (NF-\u03baB) activation. Treatment of NB-monocyte cocultures with clinical-grade etanercept completely abrogated release of IL-6, granulocyte colony-stimulating factor (G-CSF), IL-1\u03b1, and IL-1\u03b2 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-\u03b1 signaling in patients with NB that relapsed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005478","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T08:41:16Z","timestamp":1678178476000},"page":"e005478","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Interaction between tumor cell TNFR2 and monocyte membrane-bound TNF-\u03b1 triggers tumorigenic inflammation in neuroblastoma"],"prefix":"10.1136","volume":"11","author":[{"given":"Julie 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Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Balzeau","sequence":"additional","affiliation":[{"name":"Center for Advanced Innate Cell Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel A","family":"Barrag\u00e1n","sequence":"additional","affiliation":[{"name":"Center for Advanced Innate Cell Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengwen","family":"Tian","sequence":"additional","affiliation":[{"name":"Center for Advanced Innate Cell Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica J","family":"Di Pierro","sequence":"additional","affiliation":[{"name":"Center for Advanced Innate Cell Therapy, Department of 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