Anke S. Lonsdorf

Cumulative ultraviolet radiation exposure and chronic immunosuppression are major risk factors for keratinocyte cancers. Squamous cell carcinomas, the most frequent malignancies following solid organ transplantation, show markedly increased incidence and aggressiveness in transplant recipients. While posttransplant dermatologic surveillance is well established, pretransplant skin cancer prevention remains insufficiently addressed. This monocentric cross-sectional study (August 2023 to August 2025) assessed skin cancer and sun protection knowledge in adult transplant candidates undergoing dermatologic screening at a university hospital dermatology outpatient clinic, using the validated 25-item Skin Cancer and Sun Knowledge (SCSK) Scale, supplemented by questions on immunosuppression-related risk awareness and self-perceived knowledge adequacy. Immunosuppression-naive transplant candidates constituted the primary cohort; immunosuppression-experienced transplant candidates served as reference. Descriptive and nonparametric analyses were performed. Among 154 transplant candidates (144 immunosuppression-naive and 10 immunosuppression-experienced), immunosuppression-naive (mean age: 52.2 years; 69.4% male) demonstrated significantly lower SCSK scores than immunosuppression-experienced (13.6 vs. 16.9; P = 0.018). Deficits were greatest regarding tanning behavior and prevention, while symptom recognition was poor across both groups. Only 59.0% of immunosuppression-naive transplant candidates recognized immunosuppression as major skin cancer risk factor, and 29.2% felt adequately informed. Higher knowledge was associated with personal ( P = 0.031) or family ( P < 0.001) history of skin cancer, regular screenings ( P < 0.001), and lighter Fitzpatrick skin types ( P = 0.011). Transplant candidates, particularly those without prior immunosuppression, exhibit substantial deficits in skin cancer and sun protection knowledge. The pretransplant phase represents a critical, underutilized opportunity for early, structured dermatologic education before lifelong immunosuppression and increased cancer risk.

Organ transplant recipients (OTRs) face an elevated risk of skin cancer due to ultraviolet radiation (UVR) exposure and the need for chronic immunosuppression. Patient education is essential for early skin cancer detection and prevention. This cross-sectional study evaluated knowledge and attitudes regarding sun protection and skin cancer among 177 OTRs during their routine check-up at a specialized dermatologic outpatient clinic in a German University Hospital, using the validated Skin Cancer and Sun Knowledge (SCSK) scale. Demographic, clinical and transplant-related variables were analysed to identify factors associated with specific knowledge gaps. The mean SCSK score was 16.59 (standard deviation, SD±3.96). While most patients understood basic sun protection, key deficits were noted in their understanding of tanning risks, the meaning of sun protection factor (SPF) and symptoms of skin cancer. Heart transplant recipients (p=0.002) and those with immunosuppression >3 years (p=0.028) had significantly lower scores indicating inferior knowledge. Male sex and age 60 years were also associated with lower knowledge levels. Self-reported “well-informed” patients scored significantly higher (p=0.003). Despite specialized routine dermatologic care, knowledge gaps persist in high-risk subgroups of OTRs, highlighting the need for targeted, longitudinal education strategies in interdisciplinary transplant aftercare.

Merkel cell carcinoma is a rare, aggressive skin cancer in which Merkel cell polyoma virus (MCPyV) is frequently pathogenically involved. After failure of anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy, therapeutic options for advanced disease are limited. The contribution of the coinhibitory checkpoint molecule T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), a regulator of exhausted CD8+ T cells, to the immunosuppressive Merkel cell carcinoma microenvironment is understudied. This study evaluated the immunohistochemical expression of tumour (Tumor Proportion Score, TPS) and infiltrating immune cells (Immune Cell Score, ICS) for programmed cell death ligand 1, TIGIT, its high-affinity receptor CD155, and CD8 in 21 primary Merkel cell carcinoma and 6 metastases. Unlike CD155, TIGIT was abundantly expressed by tumour and immune cells and independent of the MCPyV status, determined by RT-PCR. Programmed cell death ligand 1+ immune cells were significantly increased in TIGIT TPS-positive and MCPyV-positive primary MCC along with significant intercorrelations of programmed cell death ligand 1 and TIGIT immune cell expression and CD8+ infiltrates. Programmed cell death ligand 1 IC-positivity correlated with superior disease-specific survival. The data indicate that TIGIT may contribute to local immune dysfunction in Merkel cell carcinoma, beyond programmed cell death ligand 1 and independent of MCPyV, and provide a rationale to further explore TIGIT as a potential target for Merkel cell carcinoma immunotherapy.

Beyond established anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) and its ligand CD155 are promising novel inhibitory immune checkpoint targets in human malignancies. Yet, in cutaneous squamous cell carcinoma, evidence on the collective expression patterns of these inhibitory immune checkpoints is scarce. Complete tumour sections of 36 cutaneous squamous cell carcinoma, 5 cutaneous metastases and 9 keratoacanthomas, a highly-differentiated, squamoproliferative tumour, with disparately benign biologic behaviour, were evaluated by immunohistochemistry for expression of programmed cell death ligand 1 (Tumor Proportion Score, Immune Cell Score), TIGIT, CD155 and CD8⁺ immune infiltrates. Unlike keratoacanthomas, cutaneous squamous cell carcinoma displayed a strong positive correlation of programmed cell death ligand 1 Tumor Proportion Score and CD115 expression (p < 0.001) with significantly higher programmed cell death ligand 1 Tumor Proportion Score (p < 0.001) and CD155 expression (p < 0.01) in poorly differentiated G3-cutaneous squamous cell carcinoma compared with keratoacanthomas. TIGIT⁺ infiltrates were significantly increased in programmed cell death ligand 1 Immune Cell Score positive primary tumours (p = 0.05). Yet, a strong positive correlation of TIGIT expression with CD8⁺ infiltrates was only detected in cutaneous squamous cell carcinoma (p < 0.01), but not keratoacanthomas. Providing a comprehensive overview on the collective landscape of inhibitory immune checkpoint expression, this study reveals associations of novel inhibitory immune checkpoint with CD8⁺ immune infiltrates and tumour differentiation and highlights the TIGIT/CD155 axis as a potential new target for cutaneous squamous cell carcinoma immunotherapy.

Long-lived species suppress cancer despite accumulating somatic mutations throughout life, but how this is achieved in renewing tissues remains unclear. Here, we show that naked mole-rat skin uncouples high cellular turnover from cancer risk through coordinated epithelial and stromal mechanisms that constrain clonal outgrowth and suppress tumor-promoting inflammation. Despite elevated epidermal proliferation and mutational burden, naked mole-rat skin maintains tissue integrity through an expanded pool of early committed progenitor (hybrid) cells and replication-coupled genome maintenance pathways. Under chronic carcinogenic stress, undifferentiated basal cells replenish the hybrid progenitor pool. This dilutes initiated clones and permits only limited selective expansion of rare cancer gene–mutant clones. Depletion of the hybrid compartment shifts this protective state toward clonal expansion and inflammatory activation. These expanding clones are further constrained by a highly tumor-suppressive stromal microenvironment, driven by fibroblasts that adopt a metabolically restricted, non-inflammatory program. Together, our data uncover a multi-layered tumor-suppressive strategy that couples turnover-driven regeneration with an anti-permissive stromal niche to prevent malignant progression under mutagenic stress.

Keratinocyte cancers (KC) are the most prevalent malignancies in fair‐skinned populations, posing a significant medical and economic burden to health systems. KC originate in the epidermis and mainly comprise basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Here, we combined single‐cell multi‐omics, transcriptomics, and methylomics to investigate the epigenomic dynamics during epidermal differentiation. We identified ~3,800 differentially accessible regions between undifferentiated and differentiated keratinocytes, corresponding to regulatory regions associated with key transcription factors. DNA methylation at these regions defined AK/cSCC subtypes with epidermal stem cell‐ or keratinocyte‐like features. Using cell‐type deconvolution tools and integration of bulk and single‐cell methylomes, we demonstrate that these subclasses are consistent with distinct cells‐of‐origin. Further characterization of the phenotypic traits of the subclasses and the study of additional unstratified KC entities uncovered distinct clinical features for the subclasses, linking invasive and metastatic KC cases with undifferentiated cells‐of‐origin. Our study provides a thorough characterization of the epigenomic dynamics underlying human keratinocyte differentiation and uncovers novel links between KC cells‐of‐origin and their prognosis.

Background: The risk for keratinocyte cancer is dramatically increased in solid organ transplant recipients (OTR) with a first post-transplant keratinocyte cancer conferring a high risk for subsequent keratinocyte cancer arising with accelerated dynamics. Despite cumulative ultraviolet radiation (UVR) being the primary responsible environmental carcinogen reduced compliance with photoprotective measures among OTR has been reported. Risk assessment tools could help guide clinical decision-making and targeted prevention strategies for patients at particularly high risk for post-transplant keratinocyte cancer. Objectives: To evaluate cumulative sun exposure by means of an assigned total sun burden (TSB) score, sunscreen use and associated risk factors for keratinocyte cancer in the post-transplantation phase of OTR. Methods: A retrospective single-center cohort study analyzing medical records and standardized questionnaires of 290 OTR cared for at a German dermatology transplant clinic. Results: Significantly lower TSB scores were noted in OTR not developing a first keratinocyte cancer compared to OTR developing keratinocyte cancer during their follow-up period (P = 0.005). Regression analysis assigned a significantly higher risk for the development of first keratinocyte cancer to OTR with TSB scores >10. In total 70.7% of OTR with a history of ≥1 keratinocyte cancer reported intermittent sunscreen use, while daily sunscreen use was overall associated with female gender (21.3%) and age >30 years (17.6%). Conclusions: The risk of OTR for developing keratinocyte cancer is reflected by their UV-exposure patterns, which may be assessed by the TSB-score, a scored risk assessment tool. Complementing clinical data, the TSB score may help clinicians to identify OTR at particularly high risk for keratinocyte cancer and to endorse intensified prevention strategies and dermato-oncologic care.

Pain and inferior efficacy are major limiting factors of conventional photodynamic therapy for the field treatment of actinic keratoses in immunosuppressed organ transplant recipients. This prospective randomized controlled study evaluates the efficacy and tolerability of ablative fractional laser system pretreatment combined with low-irradiance photodynamic therapy (18.5 mW/cm2) compared with conventional photodynamic therapy (61.67 mW/cm2) in the treatment of actinic keratoses on the face and scalp in organ transplant recipients, using a red light-emitting diode lamp at a total light dose of 37 J/cm2. Low-irradiance photodynamic therapy combined with Er:YAG pretreatment achieved a significantly superior lesion response rate (mean ± standard deviation 77.3 ± 23.6%) compared with conventional photodynamic therapy (61.8 ± 21.4%; p = 0.025) in intra-individual fields at 3 months without negatively impacting pain (p = 0.777) or cosmetic outcome (p = 0.157).

Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4⁺, CD8⁺ and PD-1⁺ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy.

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