{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:14:03Z","timestamp":1791335643023,"version":"4.3.1"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"9","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009812","name":"Princess Margaret Cancer Foundation","doi-asserted-by":"publisher","award":["2021"],"award-info":[{"award-number":["2021"]}],"id":[{"id":"10.13039\/100009812","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,2,28]]},"abstract":"<jats:p>\n                    Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal\/pleural macrophages (SPM), and the tissue-resident large peritoneal\/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in\u00a0vivo and in\u00a0vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing\u00a0analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial\u2013mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-\u03b1\/NFkB signaling pathways, LPM activated the IFN-\u03b3 response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes,\n                    <jats:italic>TREM2, STAB1, LAIR1, GPNMB<\/jats:italic>\n                    , and\n                    <jats:italic>MARCO<\/jats:italic>\n                    , could potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2210836120","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T13:39:56Z","timestamp":1677159596000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["Defining and targeting tumor-associated macrophages in malignant mesothelioma"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4803-9361","authenticated-orcid":false,"given":"Licun","family":"Wu","sequence":"first","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"},{"name":"Princess Margaret Cancer Centre, 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1239-0857","authenticated-orcid":false,"given":"Amin","family":"Zia","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada"},{"name":"dYcode Inc., Toronto, ON L6C 2R9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Allen","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6016-1645","authenticated-orcid":false,"given":"Veronique","family":"Serre-Beinier","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospitals of Geneva, Geneva 1205, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9128-5459","authenticated-orcid":false,"given":"Michele","family":"De Palma","sequence":"additional","affiliation":[{"name":"Swiss Federal Institute of Technology in Lausanne (Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne), Lausanne 1015, Switzerland"},{"name":"Agora Research Cancer Centre, Lausanne 1005, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3408-0294","authenticated-orcid":false,"given":"Emanuela","family":"Felley-Bosco","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular 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