Immune checkpoint inhibitors have revolutionized treatment of advanced melanoma, but commonly cause serious immune-mediated complications. The clinical ambition of reserving more aggressive therapies for patients least likely to experience immune-related adverse events (irAE) has driven an extensive search for predictive biomarkers. Here, we externally validate the performance of 59 previously reported markers of irAE risk in a new cohort of 110 patients receiving Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA-4) therapy. Alone or combined, the discriminatory value of these routine clinical parameters and flow cytometry biomarkers was poor. Unsupervised clustering of flow cytometry data returned four T cell subsets with higher discriminatory capacity for colitis than previously reported populations, but they cannot be considered as reliable classifiers. Although mechanisms predisposing some patients to particular irAEs have been described, we are presently unable to capture adequate information from pre-therapy flow cytometry and clinical data to reliably predict risk of irAE in most cases.

Soluble CD46 (sCD46) has recently been shown to be an effective biomarker of steatotic liver disease (SLD), which is highly prevalent in the western world. Since SLD directly affects outcomes after major hepatectomies and liver transplantation, accurate appraisal of this condition is crucial before liver surgery. In the present study, we asked whether sCD46 measurement in patient plasma could augment the pre-surgical prediction of SLD performed by contrast-enhanced computed tomography. Our data show that combined performance of these tests reveals an area under the curve for the prediction of high-grade SLD of 0.956. After cross-validation, our clinical score leads to an accuracy of 95.12% to detect severe steatosis. Therefore, sCD46 is a promising biomarker for optimizing pre-surgical decision-making assessments, with the aim to identify patients that could benefit from alternative treatment options.