Immune checkpoint inhibitors (ICI) have revolutionized melanoma treatment. However, a large proportion of patients do not benefit from ICI therapy. In this study, we profiled circulating proteins (~700 proteins) in serum samples from 39 stage IIIB–C melanoma patients undergoing neoadjuvant ICI therapy. Samples were taken at three time points (pre-treatment, early during ICI treatment and prior to surgery). Of the 39 patients, 27 had major pathological response (MPR), three had partial PR (pPR), while nine had pathological non-response (pNR).
We identified 27 proteins that were significantly altered (log2 fold change (FC) > 0.58, adjusted p value < 0.05), from pre-treatment to early during ICI treatment in patients with MPR. However, no proteins met this cutoff in patients with pNR. Gene Set Enrichment Analysis (GSEA) of log2 FC-ranked proteins comparing pre-treatment to early during ICI treatment revealed enrichment in five biological pathways (e.g., positive regulation of immune response). These pathways were distinct to each patient group, with MPR patients showing enrichment in pathways like innate immune response, while pNR patients showed changes in pathways related to lymphocyte differentiation. We are currently developing a protein signature to assess its potential in predicting patients likely to benefit from neoadjuvant ICI therapy. This study highlights circulating proteins as potential biomarkers to predict ICI response in stage III melanoma patients.