{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:31:34Z","timestamp":1792452694343,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:00:00Z","timestamp":1750377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>To discover immune response-associated gene expressions related to brain metastases of skin melanomas, we analyzed a group of fifteen primary skin melanomas consisting of five tumors from patients who did not develop systemic metastases (NM); ten from patients with systemic metastasis of which five with (BM), and five without brain involvement (OOM). Regions of interest (ROIs) harboring tumor cells only; immune cells only; or immune cell infiltration in tumor cell regions, were separately analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>we profiled the tumor immune microenvironment (TIME) of primary skin melanomas by using a panel of 77 immune response-related oligo-nucleotide targets in the GeoMx Digital Spatial profiler (Nanostring Technologies).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Melanomas from patients who developed brain metastases contained significantly higher levels of (CD45+) immune cells and overexpressed fibronectin and CTLA-4 in all ROIs compared to the melanomas that had metastasized to other sites than the brain (p&amp;lt;0.05). Distant metastases were accompanied by lower expression of CD137 (4-1BB). Downregulation of VISTA, IDO1 and ICOS was associated with melanomas that gave rise to distant metastases including brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Lower expression of CD137 (4-1BB) is linked with the formation of distant metastases and the expressions of fibronectin and CTLA-4 herald the formation of brain metastasis in particular.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1578986","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T05:23:33Z","timestamp":1750397013000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Overexpression of CTLA-4 and fibronectin, and lower expression of CD137 (4-1BB) is associated with brain metastasis of primary skin melanomas. An analysis of local immune response by digital spatial profiling"],"prefix":"10.3389","volume":"16","author":[{"given":"Shiva","family":"Najjary","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur al","family":"Amery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Vadgama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander C. J.","family":"van Akkooi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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