The underlying molecular mechanisms of the aberrant expression of components of the HLA class I antigen processing and presentation machinery (APM) in tumors leading to evasion from T cell-mediated immune surveillance could be due to posttranscriptional regulation mediated by microRNAs (miRs). So far, some miRs controlling the expression of different APM components have been identified. Using in silico analysis and an miR enrichment protocol in combination with small RNA sequencing, miR-26b-5p and miR-21-3p were postulated to target the 3′ untranslated region (UTR) of the peptide transporter TAP1, which was confirmed by high free binding energy and dual luciferase reporter assays. Overexpression of miR-26b-5p and miR-21-3p in melanoma cells downregulated the TAP1 protein and reduced expression of HLA class I cell surface antigens, which could be reverted by miR inhibitors. Moreover, miR-26b-5p overexpression induced a decreased T cell recognition. Furthermore, an inverse expression of miR-26b-5p and miR-21-3p with TAP1 was found in primary melanoma lesions, which was linked with the frequency of CD8⁺ T cell infiltration. Thus, miR-26-5p and miR-21-3p are involved in the HLA class I-mediated immune escape and might be used as biomarkers or therapeutic targets for HLA class I^low melanoma cells.

Melanomas are genetically and metabolically heterogeneous, which influences therapeutic efficacy and contributes to the development of treatment resistance in patients with metastatic disease. Metabolite phenotyping helps to better understand complex metabolic diseases, such as melanoma, and facilitates the development of novel therapies. Our aim was to characterize the tumor and plasma metabolomes of mice bearing genetically different melanoma xenografts. We engrafted the human melanoma cell lines A375 (BRAF mutant), WM47 (BRAF mutant), WM3000 (NRAS mutant), and WM3311 (BRAF, NRAS, NF1 triple-wildtype) and performed a broad-spectrum targeted metabolomics analysis of tumor and plasma samples obtained from melanoma-bearing mice as well as plasma samples from healthy control mice. Differences in ceramide and phosphatidylcholine species were observed between melanoma subtypes irrespective of the genetic driver mutation. Furthermore, beta-alanine metabolism differed between melanoma subtypes and was significantly enriched in plasma from melanoma-bearing mice compared to healthy mice. Moreover, we identified beta-alanine, p-cresol sulfate, sarcosine, tiglylcarnitine, two dihexosylceramides, and one phosphatidylcholine as potential melanoma biomarkers in plasma. The present data reflect the metabolic heterogeneity of melanomas but also suggest a diagnostic biomarker signature for melanoma screening.

Basal cell carcinoma (BCC) is the most common form of skin cancer worldwide. Although most BCCs can be treated by relatively simple surgical or nonsurgical methods, some patients with BCC may eventually develop advanced disease which can either be locally destructive or even include metastatic spread. The present review summarizes the current literature on the treatment of both early and advanced BCC with a focus on the hedgehog inhibitor vismodegib which has become an integral part of the management of patients with advanced BCC since its regulatory approval in 2012.

Aims: Despite their low individual metastatic potential, thin melanomas (≤1 mm Breslow thickness) contribute significantly to melanoma mortality overall. Therefore, identification of prognostic biomarkers is particularly important in this subgroup of melanoma. Prompted by preclinical results, we investigated cyclin D1 protein and Ki‐67 expression in in‐situ, metastatic and non‐metastatic thin melanomas.Methods and results: Immunohistochemistry was performed on 112 melanoma specimens, comprising 22 in situ, 48 non‐metastatic and 42 metastatic thin melanomas. Overall, epidermal and dermal cyclin D1 and Ki‐67 expression were semiquantitatively evaluated by three independent investigators and compared between groups. Epidermal Ki‐67 expression did not differ statistically in in‐situ and invasive melanoma (P = 0.7). Epidermal cyclin D1 expression was significantly higher in thin invasive than in in‐situ melanoma (P = 0.003). No difference was found in cyclin D1 expression between metastatic and non‐metastatic invasive tumours. Metastatic and non‐metastatic thin melanomas did not show significant differences in epidermal expression of Ki‐67 and cyclin D1 (P = 0.148 and P = 0.611, respectively). In contrast, strong dermal expression of Ki‐67 was more frequent in metastatic than non‐metastatic samples (28.6 versus 8.3%, respectively, P = 0.001). The prognostic value of dermal Ki‐67 expression was confirmed by multivariate analysis (P = 0.047).Conclusion: We found an increased expression of cyclin D1 in invasive thin melanomas compared to in‐situ melanomas, which supports a potential role of this protein in early invasion in melanoma, as suggested by preclinical findings. Moreover, our results confirm that high dermal Ki‐67 expression is associated with an increased risk of development of metastasis in thin melanoma and could possibly serve as a prognostic biomarker in clinical practice, especially if combined with additional methods.

CXCL13 is a potent chemoattractant cytokine that promotes the migration of cells expressing its cognate receptor, CXCR5. Accordingly, T follicular helper cells and B cells migrate towards B cell follicles in lymph nodes, where the resulting spatial proximity promotes B cell/T cell interaction and antibody formation. Moreover, effector cells of the CXCL13/CXCR5-associated immune axis express PD-1, with corresponding circulating cells occurring in the blood. The formation of so-called ectopic or tertiary lymphoid structures, recently detected in different cancer types, represents an integral part of this axis, particularly in the context of its emerging role in anti-tumor defense. These aspects of the CXCL13/CXCR5-associated immune axis are highlighted in this review, which focuses on cutaneous malignant melanoma. Specifically, we elaborate on the role of this important immune axis as a possible ancillary target of immune checkpoint inhibition with anti-PD-1 antibodies in different therapeutic settings and as a potential source of predictive biomarkers regarding treatment efficacy.

The collateral damage caused by COVID-19 pandemic-associated public health and governmental measures on patient care has been increasingly assessed in various oncological and non-oncological clinical settings. In order to investigate potential adverse effects in the field of melanoma the present study analyzed the characteristics of primary melanoma diagnoses at an Austrian dermato-pathological referral center before, during, and after the first coronavirus-related lockdown in March 2020. As suspected, we found significant temporary reductions in the number of newly diagnosed melanomas in 2020 compared to previous years, in particular, during the first lockdown period.