{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T08:38:33Z","timestamp":1787992713162,"version":"build-2784847793"},"reference-count":117,"publisher":"The Company of Biologists","issue":"8","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100014069","name":"Funda\u00e7\u00e3o Champalimaud","doi-asserted-by":"crossref","award":["RC168"],"award-info":[{"award-number":["RC168"]}],"id":[{"id":"10.13039\/501100014069","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Lisbon Regional Operational Programme","award":["LISBOA-01-0145-FEDER-022170"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-022170"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["FCT-PTDC\/MEC-ONC\/31627\/2017"],"award-info":[{"award-number":["FCT-PTDC\/MEC-ONC\/31627\/2017"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["PD\/BD\/138203\/2018"],"award-info":[{"award-number":["PD\/BD\/138203\/2018"]}]},{"name":"Calouste Gulbenkian Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>The Bacillus Calmette\u2013Gu\u00e9rin (BCG) vaccine is the oldest cancer immunotherapeutic agent in use. Despite its effectiveness, its initial mechanisms of action remain largely unknown. Here, we elucidate the earliest cellular mechanisms involved in BCG-induced tumor clearance. We developed a fast preclinical in vivo assay to visualize in real time and at single-cell resolution the initial interactions among bladder cancer cells, BCG and innate immunity using the zebrafish xenograft model. We show that BCG induced the recruitment and polarization of macrophages towards a pro-inflammatory phenotype, accompanied by induction of the inflammatory cytokines tnfa, il1b and il6 in the tumor microenvironment. Macrophages directly induced apoptosis of human cancer cells through zebrafish TNF signaling. Macrophages were crucial for this response as their depletion completely abrogated the BCG-induced phenotype. Contrary to the general concept that macrophage anti-tumoral activities mostly rely on stimulating an effective adaptive response, we demonstrate that macrophages alone can induce tumor apoptosis and clearance. Thus, our results revealed an additional step to the BCG-induced tumor immunity model, while providing proof-of-concept experiments demonstrating the potential of this unique model to test innate immunomodulators.<\/jats:p>","DOI":"10.1242\/dmm.050693","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T09:02:03Z","timestamp":1723107723000},"source":"Crossref","is-referenced-by-count":16,"title":["Macrophages directly kill bladder cancer cells through TNF signaling as an early response to BCG therapy"],"prefix":"10.1242","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9149-3960","authenticated-orcid":false,"given":"Mayra Fernanda","family":"Mart\u00ednez-L\u00f3pez","sequence":"first","affiliation":[{"name":"Cancer Research Group (CRG) 1 , Faculty of Medicine , , Quito 170124, Ecuador"},{"name":"Universidad de las Am\u00e9ricas 1 , Faculty of Medicine , , Quito 170124, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3617-4470","authenticated-orcid":false,"given":"C\u00e1tia Rebelo","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Champalimaud Research, Champalimaud Foundation 2 , Av. Brasilia, Lisbon 1400-038, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5397-2550","authenticated-orcid":false,"given":"M\u00e1rcia","family":"Fontes","sequence":"additional","affiliation":[{"name":"Champalimaud Research, Champalimaud Foundation 2 , Av. Brasilia, Lisbon 1400-038, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2113-4318","authenticated-orcid":false,"given":"Raquel Valente","family":"Mendes","sequence":"additional","affiliation":[{"name":"Champalimaud Research, Champalimaud Foundation 2 , Av. Brasilia, Lisbon 1400-038, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9866-8268","authenticated-orcid":false,"given":"Stefan H. E.","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Infection Biology 3 , Berlin 10117, Germany"},{"name":"Max Planck Institute for Multidisciplinary Sciences 4 , G\u00f6ttingen 37077, Germany"},{"name":"Hagler Institute for Advanced Study, Texas A&M University 5 , College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5550-2428","authenticated-orcid":false,"given":"Rita","family":"Fior","sequence":"additional","affiliation":[{"name":"Champalimaud Research, Champalimaud Foundation 2 , Av. Brasilia, Lisbon 1400-038, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"2024090515390055300_DMM050693C1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.chom.2017.12.010","article-title":"BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity","volume":"23","author":"Arts","year":"2018","journal-title":"Cell Host Microbe"},{"key":"2024090515390055300_DMM050693C2","doi-asserted-by":"publisher","first-page":"l5770","DOI":"10.1136\/bmj.l5770","article-title":"Is Mycobacterium tuberculosis infection life long?","volume":"367","author":"Behr","year":"2019","journal-title":"BMJ"},{"key":"2024090515390055300_DMM050693C3","first-page":"31","article-title":"BCG internalization in human bladder cancer cell lines, especially with regard to cell surface-expressed fibronectin","volume":"31","author":"Bevers","year":"2000","journal-title":"Aktuelle Urol."},{"key":"2024090515390055300_DMM050693C4","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1016\/j.juro.2008.11.124","article-title":"Molecular analyte profiling of the early events and tissue conditioning following intravesical bacillus calmette-guerin therapy in patients with superficial bladder cancer","volume":"181","author":"Bisiaux","year":"2009","journal-title":"J. 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