{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:37:18Z","timestamp":1779881838963,"version":"3.53.1"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,11,30]],"date-time":"2024-11-30T00:00:00Z","timestamp":1732924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-\u03b2 pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-\u03b2 signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Method<\/jats:title>\n                  <jats:p>The activity of 8 signaling pathways (TGF-\u03b2, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK\/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-\u03b2 pathway activation was conducted by determining levels of phosphorylated SMAD2.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The mean TGF-\u03b2 PAS of responders vs non-responders was 53.9 vs 56.8 (P\u2005=\u20050.265). No significant relation with progression-free survival was detected for TGF-\u03b2 activity (P\u2005=\u20050.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P\u2005=\u20050.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P\u2005=\u20050.033) and worse progression-free survival (HR 1\u20131.1, P\u2005=\u20050.012).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>TGF-\u03b2 pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cei\/uxae108","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T03:48:17Z","timestamp":1734061697000},"source":"Crossref","is-referenced-by-count":4,"title":["Exploring the relation between TGF-\u03b2 pathway activity and response to checkpoint inhibition in patients with metastatic melanoma"],"prefix":"10.1093","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4069-3932","authenticated-orcid":false,"given":"Stefan G","family":"van Ravensteijn","sequence":"first","affiliation":[{"name":"Radboud University Medical Center Department of Medical Oncology, , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avital L","family":"Amir","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Department of Pathology, , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele V F","family":"Tauriello","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Department of Medical BioSciences, , Nijmegen ,","place":["the Netherlands"]},{"name":"Erasmus MC Cancer Institute, University Medical Center Department of Medical Oncology, , Rotterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla M L","family":"van Herpen","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Department of Medical Oncology, , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marye J","family":"Boers-Sonderen","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Department of Medical Oncology, , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne J W","family":"Wesseling","sequence":"additional","affiliation":[{"name":"InnoSIGN B.V. 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