Multiomics analysis reveals a Type III driven immune response in immunotherapy-induced toxicity in melanoma and identifies potential new therapeutic targets.

Immune checkpoint inhibitors (ICIs) are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events (irAEs). Proteomic analysis and multiplex cytokine/chemokine assay from serum at baseline and at irAEs onset in 82 patients indicated aberrant T-cell activity with differential expression of Type I and III immune signatures. This was in line with an increase in the proportions of monocytes and decrease of IL-17A producing CD4+ T-cells in the peripheral blood in single cell RNA sequencing. Multiplex immunohistochemistry and spatial transcriptomics on ICI-induced skin rash and colitis showed increase in the proportion of CD4+ T-cells with IL-17A expression. Anti-IL17A mAbs were administered in two patients with myocarditis, colitis and skin rash with resolution of the irAE. This study demonstrates the potential role of Type III CD4+ T-cells in the irAEs development and provides proof-of-principle evidence to support a clinical trial examining anti-IL17A in their management.