{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:27:55Z","timestamp":1791559675744,"version":"4.3.4"},"reference-count":35,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T00:00:00Z","timestamp":1737417600000},"content-version":"unspecified","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PNRR-MAD-2022-12375947"],"award-info":[{"award-number":["PNRR-MAD-2022-12375947"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2019-12371549."],"award-info":[{"award-number":["RF-2019-12371549."]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["21147-ISM"],"award-info":[{"award-number":["21147-ISM"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 21179"],"award-info":[{"award-number":["IG 21179"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministero dell'Istruzione, dell'Universit\u00e0 e della Ricerca","award":["PRIN 220228KZKE3"],"award-info":[{"award-number":["PRIN 220228KZKE3"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,1,2]]},"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>ACKR2 is an atypical chemokine receptor that plays a significant role in regulating inflammation by binding to inflammatory CC chemokines and facilitating their degradation. Previous findings suggest that the genetic absence of ACKR2 leads to heightened tumor growth in inflammation-driven models. Conversely, mice lacking ACKR2 exhibit protection against lung metastasis in melanoma and breast cancer models. This study aims to explore the specific cell types expressing ACKR2 and their relative contributions to the protection against lung metastasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ACKR2 expression was studied by the generation of an inducible and conditional knockout (KO) mouse expressing two reporter genes, luciferase and TdTomato visible by In Vivo Imaging System, flow cytometry and immunofluorescence. Gene expression in lung endothelial cells (ECs) was investigated by RNA sequencing analysis. In vivo models of lung metastasis and inflammation were performed in wild-type (WT) and conditional KO mice by intravenous injection of melanoma and colon cancer cell lines; the induction of acute lung injury model was done by intranasal injection of lipopolysaccharide (LPS). Leukocytes infiltrating lung metastasis were studied by fluorescence-activated cell sorting (FACS) analysis. The serum chemokine levels were studied with a multiplex ELISA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The analysis of the reporter mouse revealed that ACKR2 is expressed by lymphatic endothelial cells (LECs) in most murine organs. However, uniquely in the lungs, ACKR2 expression is observed in blood endothelial cells (BECs), specifically in capillaries known as aerocytes specialized for regulating leukocyte trafficking. Selective deletion of Ackr2 from ECs (ACKR2\n                      <jats:sup>\u0394Cdh5<\/jats:sup>\n                      mice) but not from LECs (ACKR2\n                      <jats:sup>\u0394Prox1<\/jats:sup>\n                      mice) resulted in protection in models of melanoma and colorectal cancer lung metastasis. This protection was associated with an increased presence of activated T lymphocytes infiltrating the lungs compared with WT mice. Additionally, in a model of acute lung injury, mice with selective deletion from the endothelial compartment exhibited heightened extravasation of T lymphocytes compared with both ACKR2 KO and WT mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results indicate that ACKR2 is selectively expressed by lung vascular capillaries (aerocytes) that are devoted to the regulation of leukocyte extravasation. Selective ACKR2 targeting in this compartment, by modulating chemokine availability, promotes T lymphocyte extravasation resulting in reduced lung metastases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-009467","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T01:45:23Z","timestamp":1737510323000},"page":"e009467","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Selective expression and significance of ACKR2 in lung aerocytes"],"prefix":"10.1136","volume":"13","author":[{"given":"Francesca","family":"Albano","sequence":"first","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Mollica Poeta","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Zotti","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Castagna","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Felicetta","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Mesaglio","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Zaghen","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Sironi","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Capucetti","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Di Donato","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0556-6068","authenticated-orcid":false,"given":"Mattia","family":"Laffranchi","sequence":"additional","affiliation":[{"name":"Molecular Medicine, University of Rome \"La Sapienza\", Laboratory Affiliated to Institute Pasteur-Italia, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Massara","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8619-6152","authenticated-orcid":false,"given":"Roberta","family":"Carriero","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Condorelli","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvano","family":"Sozzani","sequence":"additional","affiliation":[{"name":"Molecular Medicine, University of Rome \"La Sapienza\", Laboratory Affiliated to Institute Pasteur-Italia, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Mantovani","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Locati","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3346-5333","authenticated-orcid":false,"given":"Raffaella","family":"Bonecchi","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,1,21]]},"reference":[{"key":"2025100304035211000_13.1.e009467.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120145"},{"key":"2025100304035211000_13.1.e009467.2","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.00379","article-title":"Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy","volume":"10","author":"Mollica Poeta","year":"2019","journal-title":"Front Immunol"},{"key":"2025100304035211000_13.1.e009467.3","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1176619","article-title":"The chemokine landscape: one system multiple shades","volume":"14","author":"Cecchinato","year":"2023","journal-title":"Front Immunol"},{"key":"2025100304035211000_13.1.e009467.4","doi-asserted-by":"crossref","unstructured":"Bonecchi R , Savino B , Borroni EM , et al . Chemokine decoy receptors: structure-function and biological properties. Curr Top Microbiol 2010;15\u201336. doi:10.1007\/82_2010_19","DOI":"10.1007\/82_2010_19"},{"key":"2025100304035211000_13.1.e009467.5","doi-asserted-by":"publisher","DOI":"10.1042\/BST20120246"},{"key":"2025100304035211000_13.1.e009467.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2012.08.003"},{"key":"2025100304035211000_13.1.e009467.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64035-7"},{"key":"2025100304035211000_13.1.e009467.8","article-title":"ACKR2: An Atypical Chemokine Receptor Regulating Lymphatic Biology","volume":"7","author":"Bonavita","year":"2016","journal-title":"Front Immunol"},{"key":"2025100304035211000_13.1.e009467.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607514104"},{"key":"2025100304035211000_13.1.e009467.10","doi-asserted-by":"publisher","DOI":"10.1378\/chest.11-3220"},{"key":"2025100304035211000_13.1.e009467.11","doi-asserted-by":"crossref","first-page":"8170","DOI":"10.4049\/jimmunol.181.11.8170-a","article-title":"Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1","volume":"181","author":"McKimmie","year":"2008","journal-title":"The Journal of Immunology"},{"key":"2025100304035211000_13.1.e009467.12","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2016.00224","article-title":"Atypical Chemokine Receptors and Their Roles in the Resolution of the Inflammatory Response","volume":"7","author":"Bonecchi","year":"2016","journal-title":"Front Immunol"},{"key":"2025100304035211000_13.1.e009467.13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.1.17"},{"key":"2025100304035211000_13.1.e009467.14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-344044"},{"key":"2025100304035211000_13.1.e009467.15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070608"},{"key":"2025100304035211000_13.1.e009467.16","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3MR0915-431RR"},{"key":"2025100304035211000_13.1.e009467.17","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0202"},{"key":"2025100304035211000_13.1.e009467.18","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-03080-8","article-title":"ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity","volume":"9","author":"Massara","year":"2018","journal-title":"Nat Commun"},{"key":"2025100304035211000_13.1.e009467.19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800131"},{"key":"2025100304035211000_13.1.e009467.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.002"},{"key":"2025100304035211000_13.1.e009467.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.01.015"},{"key":"2025100304035211000_13.1.e009467.22","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/s41586-020-2822-7","article-title":"Capillary cell-type specialization in the alveolus","volume":"586","author":"Gillich","year":"2020","journal-title":"Nature New Biol"},{"key":"2025100304035211000_13.1.e009467.23","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.143283","article-title":"A global live cell barcoding approach for multiplexed mass cytometry profiling of mouse tumors","volume":"6","author":"Charmsaz","year":"2021","journal-title":"JCI Insight"},{"key":"2025100304035211000_13.1.e009467.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.08.077"},{"key":"2025100304035211000_13.1.e009467.25","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.005"},{"key":"2025100304035211000_13.1.e009467.26","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1093\/jleuko\/qiae162","article-title":"Enhanced CCR2 expression by ACKR2-deficient NK cells increases tumoricidal cell therapy efficacy","volume":"116","author":"Hayes","year":"2024","journal-title":"J Leukoc Biol"},{"key":"2025100304035211000_13.1.e009467.27","doi-asserted-by":"crossref","unstructured":"Braeckel-Budimir N , et al . Combinatorial immunotherapy induces tumor-infiltrating CD8. J Immunother Cancer 2021. doi:10.1136\/jitc-2021-003614","DOI":"10.1136\/jitc-2021-003614"},{"key":"2025100304035211000_13.1.e009467.28","doi-asserted-by":"crossref","DOI":"10.3389\/fcvm.2021.619690","article-title":"Endothelial Cells in Emerging Viral Infections","volume":"8","author":"Fosse","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"2025100304035211000_13.1.e009467.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2016.06.023"},{"key":"2025100304035211000_13.1.e009467.30","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13460"},{"key":"2025100304035211000_13.1.e009467.31","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00134.2019"},{"key":"2025100304035211000_13.1.e009467.32","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00233.2017"},{"key":"2025100304035211000_13.1.e009467.33","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2024.1377913","article-title":"The atypical chemokine receptor 2 reduces T cell expansion and tertiary lymphoid tissue but does not limit autoimmune organ injury in lupus-prone B6lpr mice","volume":"15","author":"Xia","year":"2024","journal-title":"Front Immunol"},{"key":"2025100304035211000_13.1.e009467.34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-1-4939-3302-0_2","article-title":"Principles of Amnis Imaging Flow Cytometry","volume":"Biol1389","author":"Basiji","year":"2016","journal-title":"Methods Mol"},{"key":"2025100304035211000_13.1.e009467.35","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-023-40790-0","article-title":"CRUSTY: a versatile web platform for the rapid analysis and visualization of high-dimensional flow cytometry data","volume":"14","author":"Puccio","year":"2023","journal-title":"Nat Commun"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2024-009467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T11:04:10Z","timestamp":1759489450000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2024-009467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,21]]},"published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1136\/jitc-2024-009467"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2024-009467","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]}}}