Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.

Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

The therapeutically actionable long non-coding RNA 'T-RECS' is essential to cancer cells' survival in NRAS/MAPK-driven melanoma.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Immune checkpoint inhibition and targeted therapy for melanoma: A patient-oriented cross-sectional comparative multicentre study.

BACKGROUND: Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences. OBJECTIVE: Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma. METHODS: A German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list. RESULTS: Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients. CONCLUSIONS: Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment.

Image-based response assessment during immunotherapy in skin cancer.

Immune-checkpoint inhibitors and further immunotherapeutic treatment strategies have significantly extended therapy options for melanoma and other skin cancer entities over the last decade. In the context of a broader application of immunotherapeutic approaches, sufficient ways to monitor the course of the disease during therapy are required. Immunotherapies are based on different ways of modulating the immune system. This leads to complex clinical response patterns including pseudoprogression and others, requiring an adaptation of conventional diagnostic imaging tools or the introduction of novel technologies. In this review, current non-invasive imaging approaches for response assessment during immunotherapies in skin cancers as well as their limitations are discussed. To overcome present hurdles, promising alternatives to better address novel imaging features during immunotherapy are depicted giving an outlook on what can be expected in the future.

S2k Guideline - Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) - Update 2022.

Merkel cell carcinoma (MCC, ICD-O M8247/3) is a rare, malignant, primary skin tumor with epithelial and neuroendocrine differentiation. The tumor cells share many morphologic, immunohistochemical, and ultrastructural features with cutaneous Merkel cells. Nevertheless, the cell of origin of MCC is unclear. MCC appears clinically as a reddish to purple spherical tumor with a smooth, shiny surface and a soft to turgid, elastic consistency, usually showing rapid growth. Spontaneous and often complete regressions of the tumor are observed. These likely immunologically-mediated regressions explain the cases in which only lymph node or distant metastases are found at the time of initial diagnosis and why the tumor responds very well to immunomodulatory therapies even at advanced stages. Due to its aggressiveness, the usually given indication for sentinel lymph node biopsy, the indication of adjuvant therapies to be evaluated, as well as the complexity of the necessary diagnostics, clinical management should already be determined by an interdisciplinary tumor board at the time of initial diagnosis.

Adult-Onset Neurodegeneration in Nucleotide Excision Repair Disorders (NERDND ): Time to Move Beyond the Skin.

BACKGROUND: Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. OBJECTIVE: The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. METHODS: In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments. RESULTS: We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. CONCLUSIONS: We introduce NERDND as adult-onset neurodegeneration (ND ) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab).

Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.

Vemurafenib-related photosensitivity.

Increased photosensitivity is a common cutaneous adverse effect associated with the BRAF inhibitor vemurafenib. Clinically, it presents as an immediate sensation of heat and edematous erythema during sun exposure, as well as a sunburn reaction in terms of a late reaction. Phototesting has shown that the UVA range (320 nm to 400 nm), triggers both the immediate and the late reaction. In terms of pathogenesis, photochemical studies have suggested that exposure of vemurafenib to UVA radiation produces an UVA-absorbing photoproduct. In vitro studies on various cell models have also demonstrated that the phototoxic effects of vemurafenib are exclusively caused by UVA irradiation. This latter mechanism is probably responsible for the photosensitivity clinically observed in patients receiving vemurafenib. In addition, vemurafenib is able to inhibit ferrochelatase. The resulting increase in protoporphyrin IX has also been observed in some human studies involving the drug. However, it is yet unproven whether porphyrins actually contribute to the immediate skin reactions seen in individuals on vemurafenib, even though the clinical presentation is similar to that found in erythropoietic protoporphyria with a comparable pathomechanism. Other BRAF inhibitors, such as dabrafenib and encorafenib, are associated with significantly lower photosensitivity. It is essential that patients treated with vemurafenib are informed about immediate and delayed reactions potentially caused even by low doses of UVA. This includes counseling on photoprotective measures.

Knowledge and Influence of Predatory Journals in Dermatology: A Pan-Austrian Survey.

The aim of this study was to assess the knowledge and influence of predatory journals in the field of dermatology in Austria. A total of 286 physicians (50.5% men) completed a questionnaire. The vast majority of subjects read scientific articles (n = 281, 98.3%) and took them into consideration in their clinical decision-making (n = 271, 98.5% of participants that regularly read scientific literature). Open access was known by 161 (56.3%), predatory journals by 84 (29.4%), and the Beall's list by 19 physicians (6.7%). A total of 117 participants (40.9%) had been challenged by patients with results from the scientific literature, including 9 predatory papers. Participants who knew of predatory journals had a higher level of education as well as scientific experience, and were more familiar with the open-access system (p < 0.001). These results indicate that the majority of dermatologists are not familiar with predatory journals. This is particularly the case for physicians in training and in the early stages of their career.

Clinical melanoma characteristics and survival-a single-center retrospective study between 2000 and 2010.

The aim of this study was to characterize clinical, histological, and outcome features of primary melanoma in 1329 patients managed at a single-center institution between 2000 and 2010. Parameters included age at diagnosis, sex, tumor location, histology, stage, Breslow thickness, and sentinel lymph node status among others. The mean age at diagnosis was 59.1 ± 16.7 years. Women were significantly younger than men when diagnosed (57.2 vs. 61.0 years; p < 0.001). Most melanomas (83%) were diagnosed on typically sun-exposed skin areas. Superficial spreading melanoma (39.5%) was the most frequent histological subtype. The median Breslow thickness was significantly higher for men compared to women (1.10 mm vs. 0.90 mm; p = 0.018). 38.3% of patients with positive and 12.9% of patients with negative sentinel biopsies progressed. Five-year survival analysis for a sub-cohort of 577 patients showed better 5­year overall survival for woman compared to men (75.8% vs. 63.6%; p = 0.025). Our findings indicate differences in patient characteristics between men and women, and underscore the importance of early melanoma detection to prevent disease progression.