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Summary: Background: Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) by anti‐Dsg3 IgG inducing erosions in the mucosa; and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3. Objectives: To characterize the Ca2+ flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Methods: Immunoprecipitation, Ca2+ flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used. Results: PV IgG and PF IgG, but neither Dsg3‐specific monoclonal antibody (AK23) nor mPV IgG, caused Ca2+ influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (PLC) – was activated by PV IgG and PF IgG but not AK23 or mPV IgG. PLC releases inositol 1,4,5‐trisphosphate (IP3) causing IP3 receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ release‐activated channels (CRAC)‐mediated Ca2+ influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca2+ influx; ameliorated alterations of Dsg1 and Dsg3 localization, and reorganization of keratin and actin filaments; and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV IgG‐induced blister formation and redistribution of Dsg1 and Dsg3 in human skin ex vivo. Conclusions: Ca2+‐mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca2+ signalling may be a promising approach to treat epidermal manifestations of pemphigus. What is already known about this topic?Autoantibody‐induced Ca2+ signalling and activation of phospholipase C in keratinocytes has been reported as the first signalling pathway in pemphigus.Ca2+ influx correlates with the presence of autoantibodies targeting desmoglein (Dsg) 1.The role and exact mechanisms of the Ca2+ signalling pathway and its role in pemphigus pathology are unclear. What does this study add?There is an important role of the phospholipase C/Ca2+ signalling pathway in the pathogenesis of pemphigus.Relevant signal components of the Ca2+ pathway are characterized in detail.Dsg1 and Dsg3 are found to interact with signalling molecules, organizing signalling complexes that differ with respect to the presence of phosphatidylinositol 4‐kinase α, the most upstream activator of the Ca2+‐influx pathway, assigning different roles to Dsg1‐ and Dsg3‐mediated signalling. What is the translational message?Current therapies for pemphigus have a delayed onset of action. Rapidly effective therapeutic approaches that directly stabilize desmosomal adhesion are desirable.While targeting the Ca2+ flux is problematic, the role of phospholipase C in the influx identifies this molecule as a potential target for specific molecular therapy approaches.Elucidating the mechanism of Dsg1‐dependent regulation of Ca2+ influx in keratinocytes helps us to understand the different blistering patterns and the phenotypic variability seen in pemphigus. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti‐programmed death‐1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long‐term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose‐optimized ipilimumab (1 mg kg−1) combined with nivolumab (3 mg kg−1), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN‐neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far. Linked Comment: Blankenstein and van Akkooi. Br J Dermatol 2020; 183:421–422. What's already known about this topic? Neoadjuvant immunotherapy is used in resectable stage III melanoma with lymph node involvement.Neoadjuvant ipilimumab plus nivolumab is associated with a high pathological complete response (pCR) rate.Pathological response data can be used as a surrogate outcome marker, as pCR and relapse‐free survival appear to correlate.Patients with melanoma with in transit metastases were excluded from prospective clinical trials employing neoadjuvant ipilimumab plus nivolumab. What does this study add? Neoadjuvant immunotherapy was performed in three patients with lymph node and satellite or in transit metastases, and in one patient with an advanced primary and lymph node metastases.All patients achieved a radiological objective response and a pathological response (partial or complete) in all metastatic sites and in the advanced primary.To date, none of the patients has relapsed. Linked Comment: Blankenstein and van Akkooi. Br J Dermatol 2020; 183:421–422. [ABSTRACT FROM AUTHOR]