Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy
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. Pati...
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| Format: | Article |
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MDPI AG
2024-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/2/471 |
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| author | David Rafei-Shamsabadi Lena Scholten Sisi Lu Daniele Castiglia Giovanna Zambruno Andreas Volz Andreas Arnold Mina Saleva Ludovic Martin Kristin Technau-Hafsi Frank Meiss Dagmar von Bubnoff Cristina Has |
| author_facet | David Rafei-Shamsabadi Lena Scholten Sisi Lu Daniele Castiglia Giovanna Zambruno Andreas Volz Andreas Arnold Mina Saleva Ludovic Martin Kristin Technau-Hafsi Frank Meiss Dagmar von Bubnoff Cristina Has |
| author_sort | David Rafei-Shamsabadi |
| collection | DOAJ |
| description | 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 mm<sup>2</sup> 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. |
| first_indexed | 2024-03-08T11:02:11Z |
| format | Article |
| id | doaj.art-6e339ea26d1f4696b82411888b77f516 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T11:02:11Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6e339ea26d1f4696b82411888b77f5162024-01-26T15:39:16ZengMDPI AGCancers2072-66942024-01-0116247110.3390/cancers16020471Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for ImmunotherapyDavid Rafei-Shamsabadi0Lena Scholten1Sisi Lu2Daniele Castiglia3Giovanna Zambruno4Andreas Volz5Andreas Arnold6Mina Saleva7Ludovic Martin8Kristin Technau-Hafsi9Frank Meiss10Dagmar von Bubnoff11Cristina Has12Department of Dermatology, Medical Center—University of Freiburg, Faculty of Medicine, 79104 Freiburg, GermanyDepartment of Dermatology, Medical Center—University of Freiburg, Faculty of Medicine, 79104 Freiburg, GermanyDepartment of Dermatology, Medical Center—University of Freiburg, Faculty of Medicine, 79104 Freiburg, GermanyLaboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Via Monti di Creta 104, 00167 Rome, ItalyGenetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00165 Rome, ItalyDermatologie am Rhein, 4051 Basel, SwitzerlandDermatologie am Rhein, 4051 Basel, SwitzerlandDepartment of Dermatology and Venereology, University Hospital “Alexandrovska”, Faculty of Medicine, Sofia University of Medicine, 1431 Sofia, BulgariaMAGEC Nord Reference Center for Rare Skin Diseases, Department of Dermatology, Angers University Hospital, 49933 Angers, FranceDepartment of Dermatology, Medical Center—University of Freiburg, Faculty of Medicine, 79104 Freiburg, GermanyDepartment of Dermatology, Medical Center—University of Freiburg, Faculty of Medicine, 79104 Freiburg, GermanyDepartment of Dermatology, Allergology and Venerology, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, GermanyDepartment of Dermatology, Medical Center—University of Freiburg, Faculty of Medicine, 79104 Freiburg, GermanyCutaneous 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 mm<sup>2</sup> 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.https://www.mdpi.com/2072-6694/16/2/471epidermolysis bullosacollagen VIIkindlinsquamous cell carcinomaindoleamine 2,3-dioxygenaseprogrammed cell death protein-1 |
| spellingShingle | David Rafei-Shamsabadi Lena Scholten Sisi Lu Daniele Castiglia Giovanna Zambruno Andreas Volz Andreas Arnold Mina Saleva Ludovic Martin Kristin Technau-Hafsi Frank Meiss Dagmar von Bubnoff Cristina Has Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy Cancers epidermolysis bullosa collagen VII kindlin squamous cell carcinoma indoleamine 2,3-dioxygenase programmed cell death protein-1 |
| title | Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy |
| title_full | Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy |
| title_fullStr | Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy |
| title_full_unstemmed | Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy |
| title_short | Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy |
| title_sort | epidermolysis bullosa associated squamous cell carcinomas support an immunosuppressive tumor microenvironment prospects for immunotherapy |
| topic | epidermolysis bullosa collagen VII kindlin squamous cell carcinoma indoleamine 2,3-dioxygenase programmed cell death protein-1 |
| url | https://www.mdpi.com/2072-6694/16/2/471 |
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