{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T04:01:15Z","timestamp":1789876875148,"version":"4.0.1"},"reference-count":96,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T00:00:00Z","timestamp":1692403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Society of Medical Oncology (SEOM) Fellowship Program (Return Fellowship)","award":["825510, ESCALON"],"award-info":[{"award-number":["825510, ESCALON"]}]},{"name":"Spanish Society of Medical Oncology (SEOM) Fellowship Program (Return Fellowship)","award":["PI20\/00189"],"award-info":[{"award-number":["PI20\/00189"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation Program","award":["825510, ESCALON"],"award-info":[{"award-number":["825510, ESCALON"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation Program","award":["PI20\/00189"],"award-info":[{"award-number":["PI20\/00189"]}]},{"name":"Instituto de Salud Carlos III, Spain","award":["825510, ESCALON"],"award-info":[{"award-number":["825510, ESCALON"]}]},{"name":"Instituto de Salud Carlos III, Spain","award":["PI20\/00189"],"award-info":[{"award-number":["PI20\/00189"]}]},{"name":"European Regional Development Fund","award":["825510, ESCALON"],"award-info":[{"award-number":["825510, ESCALON"]}]},{"name":"European Regional Development Fund","award":["PI20\/00189"],"award-info":[{"award-number":["PI20\/00189"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. Methods: Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1\/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. Results: A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs\u201415 studies), perihilar\u2013distal CCAs (p\/dCCAs\u20147 studies), and gallbladder cancer (GBC\u20145 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI\/MMRd tumors, respectively. Conclusion: From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.<\/jats:p>","DOI":"10.3390\/cells12162098","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T01:38:31Z","timestamp":1692581911000},"page":"2098","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis"],"prefix":"10.3390","volume":"12","author":[{"given":"Giorgio","family":"Frega","sequence":"first","affiliation":[{"name":"Osteoncology, Soft Tissue and Bone Sarcomas, Innovative Therapy Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-2122","authenticated-orcid":false,"given":"Fernando P.","family":"Cossio","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry I, Center of Innovation in Advanced Chemistry (ORFEO-CINQA), University of the Basque Country\/Euskal Herriko Unibertsitatea (UPV\/EHU), Donostia International Physics Center (DIPC), 48940 Donostia-San Sebastian, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus M.","family":"Banales","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute\u2014Donostia University Hospital, University of the Basque Country (UPV\/EHU), Ikerbasque, 48940 San Sebastian, Spain"},{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31009 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Cardinale","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4748-0326","authenticated-orcid":false,"given":"Rocio I. R.","family":"Macias","sequence":"additional","affiliation":[{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4835-1259","authenticated-orcid":false,"given":"Chiara","family":"Braconi","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK"},{"name":"Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Lamarca","sequence":"additional","affiliation":[{"name":"Department of Oncology\u2014OncoHealth Institute, Instituto de Investigaci\u00f3n Sanitaria de la Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, 28040 Madrid, Spain"},{"name":"Department of Medical Oncology, The Christie NHS Foundation, Manchester, Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1016\/S0140-6736(13)61903-0","article-title":"Cholangiocarcinoma","volume":"383","author":"Razumilava","year":"2014","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Altekruse, S.F., Petrick, J.L., Rolin, A.I., Cuccinelli, J.E., Zou, Z., Tatalovich, Z., and McGlynn, K.A. 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