LAUSR

Simple Summary In this study, we thoroughly explore the clinical and biological features of immunotherapy-induced vitiligo-like depigmentation (VLD) in patients with stage III-IV melanoma receiving immunotherapy. Key findings include a distinct immune signature with an upregulation of ITGA in the VLD group, an upregulation of EDAR and downregulation of LAG3 in VLD-responders group, a longer time to VLD onset in patients pre-treated with targeted therapy, the distribution of VLD lesions primarily in sun-exposed areas as opposed to mechanically stressed areas in non-immunotherapy-related vitiligo, the predominance of a symmetrical, small-freckle lesional pattern and a prolonged progression-free survival (PFS) and overall survival (OS) in VLD patients without LDH elevation as opposed to those with LDH elevation. Abstract Vitiligo-like depigmentation (VLD) is an immune-related adverse event (irAE) of checkpoint-inhibitor (CPI) treatment, which has previously been associated with a favourable outcome. The aim of this study was to explore clinical, biological and prognostic features of melanoma patients with VLD under CPI-treatment and to explore whether they exhibit a characteristic immune response profile in peripheral blood. Melanoma patients developing VLD under CPI were included in a prospective observational single-center cohort study. We collected and analysed clinical parameters, photographs and serum from 28 VLD patients. They received pembrolizumab (36%), nivolumab (11%), ipilimumab/nivolumab (32%) or clinical trial medications (21%). We performed a high-throughput proteomics assay (Olink), in which we identified a distinct proteomic signature in VLD patients in comparison to non-VLD CPI patients. Our clinical assessments revealed that VLD lesions had a predominantly symmetrical distribution pattern, with mostly smaller “freckle-like” macules and a preferential distribution in UV-exposed areas. Patients with previous targeted therapy showed a significantly longer time lapse between CPI initiation and VLD onset compared to non-pre-treated patients (12.5 vs. 6.25 months). Therapy responders exhibited a distinct proteomic profile when compared with non-responders in VLD such as upregulation of EDAR and downregulation of LAG3. ITGA11 was elevated in the VLD-group when compared to non-VLD-CPI-treated melanoma patients. Our findings demonstrate that on a proteomic level, VLD is characterized by a distinct immune signature when compared to CPI-treated patients without VLD and that therapy responsiveness is reflected by a characteristic immune profile. The pathomechanisms underlying these findings and how they could relate to the antitumoral response in melanoma remain to be elucidated.