Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM).,However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded.,We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.,Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated.,Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.,Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab.,The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively.,We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status.,In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085).,In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996).,Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy.,Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).,Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood.,Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion.,The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown.,Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity.,We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization.,We further determined APT1 phosphorylation increases melanoma invasion in vitro, and also correlated with increased tumor grade and metastasis.,Our results further establish APT1 as an important regulator of melanoma invasion and metastatic behavior.,Inhibition of APT1 may represent a novel way to treat Wnt5a driven cancers.