Interleukin-17A immune pattern across genetic acantholytic and blistering disorders

Javid, Asal Haghighi; Li, Donglin; Technau‐Hafsi, Kristin; Has, Cristina

doi:10.1093/ced/llad012

Cited by 15 publications

(2 citation statements)

References 10 publications

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“…Similarly, KEB-SCCs showed high PD-L1 expression in tumor cells and PD-1 expression in the TME. The regulation of PD-L1 may result from transcription factors (e.g., STAT3) or cytokines (e.g., IFN, TNF, and IL-17) that are increased in DEB [45][46][47]. IDO is upregulated by tumor cells to support an immunosuppressive environment.…”

Section: Discussionmentioning

confidence: 99%

Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy

Rafei-Shamsabadi,

Scholten,

et al. 2024

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy

Rafei-Shamsabadi,

Scholten,

et al. 2024

Cancers

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“…Similarly, immunohistochemical staining of IL-17A demonstrated five- to sevenfold increase in IL-17A + cells in patients with DEB compared to healthy controls. 134 Thus, small molecules and biologics 135 targeting IL-17A, which are also commonly used to treat psoriasis, may be beneficial for some people with DEB.…”

Section: Disease-modifying or Symptomatic Control Treatmentsmentioning

confidence: 99%

Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects

Hou,

del Agua,

Lwin

et al. 2023

TCRM

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Dystrophic epidermolysis bullosa (DEB) is one of the major types of EB, a rare hereditary group of trauma-induced blistering skin disorders. DEB is caused by inherited pathogenic variants in the COL7A1 gene, which encodes type VII collagen, the major component of anchoring fibrils which maintain adhesion between the outer epidermis and underlying dermis. DEB can be subclassified into dominant (DDEB) and recessive (RDEB) forms. Generally, DDEB has a milder phenotype, while RDEB patients often have more extensive blistering, chronic inflammation, skin fibrosis, and a propensity for squamous cell carcinoma development, collectively impacting on daily activities and life expectancy. At present, best practice treatments are mostly supportive, and thus there is a considerable burden of disease with unmet therapeutic need. Over the last 20 years, considerable translational research efforts have focused on either trying to cure DEB by direct correction of the COL7A1 gene pathology, or by modifying secondary inflammation to lessen phenotypic severity and improve patient symptoms such as poor wound healing, itch, and pain. In this review, we provide an overview and update on various therapeutic innovations for DEB, including gene therapy, cell-based therapy, protein therapy, and disease-modifying and symptomatic control agents. We outline the progress and challenges for each treatment modality and identify likely prospects for future clinical impact.

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Treatment of Epidermolysis Bullosa and Future Directions: A Review

Danescu,

Negrutiu,

Has

2024

Dermatol Ther (Heidelb)

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Epidermolysis bullosa (EB) comprises rare genetic disorders characterized by skin and mucosal membrane blistering induced by mechanical trauma. Molecularly, pathogenic variants affect genes encoding proteins crucial for epidermal–dermal adhesion and stability. Management of severe EB is multidisciplinary, focusing on wound healing support, ensuring that patients thrive, and complication treatment. Despite extensive research over 30 years, novel therapeutic approaches face challenges. Gene therapy and protein therapy struggle with efficacy, while regenerative cell-based therapies show limited effects. Drug repurposing to target various pathogenic mechanisms has gained attention, as has in vivo gene therapy with drugs for dystrophic and junctional EB that were recently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). However, their high cost limits global accessibility. This review examines therapeutic advancements made over the past 5 years, exploiting a systematic literature review and clinical trial data.

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Interleukin-17A immune pattern across genetic acantholytic and blistering disorders

Cited by 15 publications

References 10 publications

Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy

Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy

Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects

Treatment of Epidermolysis Bullosa and Future Directions: A Review

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