{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:02:02Z","timestamp":1792638122908,"version":"4.5.0"},"reference-count":44,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T00:00:00Z","timestamp":1620518400000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente 2018-2020 and 2021 \"Meccanismi e"],"award-info":[{"award-number":["Ricerca Corrente 2018-2020 and 2021 \"Meccanismi e"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009886","name":"Regione Puglia","doi-asserted-by":"publisher","award":["Tecnomed \u2013 Tecnopolo per la Medicina di Precisio"],"award-info":[{"award-number":["Tecnomed \u2013 Tecnopolo per la Medicina di Precisio"]}],"id":[{"id":"10.13039\/501100009886","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,4,2]]},"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Emerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Blood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR<jats:sup>+<\/jats:sup> EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Responders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8<jats:sup>+<\/jats:sup> T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR<jats:sup>+<\/jats:sup>EV quartiles indicated that higher levels of melanoma-derived uPAR<jats:sup>+<\/jats:sup> EVs were strongly correlated with poorer progression-free survival (p&lt;0.0001) and overall survival (p&lt;0.0001). We also found a statistically significant correlation between lower levels of uPAR<jats:sup>+<\/jats:sup> EVs from both CD8<jats:sup>+<\/jats:sup> T cells and DCs and better survival.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results indicate that higher levels of tumor-derived, DC-derived and CD8<jats:sup>+<\/jats:sup> T cell-derived uPAR<jats:sup>+<\/jats:sup> EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR<jats:sup>+<\/jats:sup> EVs represent a new potential target for future therapeutic approaches.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-002372","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T12:52:34Z","timestamp":1620651154000},"page":"e002372","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":45,"title":["uPAR<sup>+<\/sup> extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients"],"prefix":"10.1136","volume":"9","author":[{"given":"Letizia","family":"Porcelli","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Guida","sequence":"additional","affiliation":[{"name":"Rare tumors and Melanoma Unit, IRCCS Istituto 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