{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:57:27Z","timestamp":1790621847942,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T00:00:00Z","timestamp":1705881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Excellent Clinician Scientists in Freiburg\u2014Education for Leadership (EXCEL at the Medical Center\u2014the Faculty of Medicine, the University of Freiburg, Germany)","award":["EXCEL2016_Kolleg.15"],"award-info":[{"award-number":["EXCEL2016_Kolleg.15"]}]},{"name":"Else Kr\u00f6ner-Fresenius-Stiftung Foundation","award":["EXCEL2016_Kolleg.15"],"award-info":[{"award-number":["EXCEL2016_Kolleg.15"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. Patients with dystrophic EB (DEB) and Kindler EB (KEB) have the highest propensity for developing SCCs. Another patient group that develops high-risk SCCs is immunosuppressed (IS) patients, especially after organ transplantation. Herein, we interrogate whether immune checkpoint proteins and immunosuppressive enzymes are dysregulated in EB-associated SCCs as an immune resistance mechanism and compare the expression patterns with those in SCCs from IS patients, who frequently develop high-risk tumors and sporadic SCCs, and immunocompetent (IC) individuals. The expression of indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and inflammatory infiltrates (CD4, CD8, and CD68) was assessed via immunohistochemistry and semi-quantitative analysis in 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 sporadic IC-SCCs. DEB-SCCs expressed significantly higher levels of IDO and PD-L1 in tumor cells and PD-1 in the tumor microenvironment (TME) compared with SCCs from IC and IS individuals. The number of CD4-positive T cells per mm2 was significantly lower in DEB-SCCs compared with IC-SCCs. KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs.<\/jats:p>","DOI":"10.3390\/cancers16020471","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T12:01:13Z","timestamp":1705924873000},"page":"471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7850-3199","authenticated-orcid":false,"given":"David","family":"Rafei-Shamsabadi","sequence":"first","affiliation":[{"name":"Department of Dermatology, Medical Center\u2014University of Freiburg, Faculty of Medicine, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Scholten","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Center\u2014University of Freiburg, Faculty of Medicine, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Center\u2014University of Freiburg, Faculty of Medicine, 79104 Freiburg, Germany"},{"name":"Department of Obstetrics and Gynaecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3501-6742","authenticated-orcid":false,"given":"Daniele","family":"Castiglia","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell\u2019Immacolata Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Via Monti di Creta 104, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Zambruno","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2017-2389","authenticated-orcid":false,"given":"Andreas","family":"Volz","sequence":"additional","affiliation":[{"name":"Dermatologie am Rhein, 4051 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Arnold","sequence":"additional","affiliation":[{"name":"Dermatologie am Rhein, 4051 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Saleva","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, University Hospital \u201cAlexandrovska\u201d, Faculty of Medicine, Sofia University of Medicine, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Martin","sequence":"additional","affiliation":[{"name":"MAGEC Nord Reference Center for Rare Skin Diseases, Department of Dermatology, Angers University Hospital, 49933 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Technau-Hafsi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Center\u2014University of Freiburg, Faculty of Medicine, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4044-9094","authenticated-orcid":false,"given":"Frank","family":"Meiss","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Center\u2014University of Freiburg, Faculty of Medicine, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"von Bubnoff","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Allergology and Venerology, University Hospital Schleswig-Holstein, Campus L\u00fcbeck, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Has","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Center\u2014University of Freiburg, Faculty of Medicine, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jaad.2008.09.035","article-title":"Epidermolysis Bullosa and the Risk of Life-Threatening Cancers: The National EB Registry Experience, 1986\u20132006","volume":"60","author":"Fine","year":"2009","journal-title":"J. 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