Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs).,Reliable biomarkers to predict response and clinical outcome are needed.,We investigated the role of melanoma-associated antibodies as predictive markers for CI therapy in two independent cohorts.,In cohort 1, a prospective study, we measured specific antibodies before treatment, after one week and after six to nine weeks of treatment.,Cohort 2 consisted of serum samples prior to CI therapy initiation.,ELISA assays were performed to quantify specific IgG directed against melanocyte differentiation antigens tyrosinase-related proteins 1 and 2 (TRP1/TYRP1 and TRP2/TYRP2), glycoprotein 100 (gp100), MelanA/MART1, and the cancer-testis antigen NY-ESO-1.,Response was defined as either complete or partial remission on CT scan according to RECIST 1.1.,In cohort 1, baseline levels of these antibodies were higher in the responder group, although statistical significance was only reached for NY-ESO-1 (p = 0.007).,In cohort 2, significantly higher antibody baseline levels for MelanA/MART1 (p = 0.003) and gp100 (p = 0.029) were found.,After pooling the results from both cohorts, higher levels of MelanA/MART1 (p = 0.013), TRP1/TYRP1 (p = 0.048), TRP2/TYRP2 (p = 0.047) and NY-ESO-1 (p = 0.005) specific antibodies at baseline were independently associated with response.,Melanoma-associated antibodies may be candidate biomarkers for response and survival in metastatic melanoma patients being treated with CIs.,These markers may be used to complement patient assessment, in combination with PD-L1 status, tumor-infiltrating lymphocytes and tumor mutational burden, with the aim to predict outcome of CI treatment in patients with metastatic melanoma.,Ethikkommission Ostschweiz, EKOS 16/079 https://ongoingprojects.swissethics.ch/runningProjects_list.php?,q=%28BASECID~contains~2016-00998%29&orderby=dBASECID.,The online version of this article (10.1186/s40425-019-0523-2) contains supplementary material, which is available to authorized users.
Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, or the combination) enhance anti-tumor immune responses, yielding durable clinical benefit in several cancer types, including melanoma.,However, a subset of patients experience immune-related adverse events (irAEs), which can be severe and result in treatment termination.,To date, no biomarker exists that can predict development of irAEs.,We hypothesized that pre-treatment antibody profiles identify a subset of patients who possess a sub-clinical autoimmune phenotype that predisposes them to develop severe irAEs following immune system disinhibition.,Using a HuProt human proteome array, we profiled baseline antibody levels in sera from melanoma patients treated with anti-CTLA-4, anti-PD-1, or the combination, and used support vector machine models to identify pre-treatment antibody signatures that predict irAE development.,We identified distinct pre-treatment serum antibody profiles associated with severe irAEs for each therapy group.,Support vector machine classifier models identified antibody signatures that could effectively discriminate between toxicity groups with > 90% accuracy, sensitivity, and specificity.,Pathway analyses revealed significant enrichment of antibody targets associated with immunity/autoimmunity, including TNFα signaling, toll-like receptor signaling and microRNA biogenesis.,Our results provide the first evidence supporting a predisposition to develop severe irAEs upon immune system disinhibition, which requires further independent validation in a clinical trial setting.,The online version of this article (10.1186/s12967-018-1452-4) contains supplementary material, which is available to authorized users.