Multiomics analyses reveal a Type III-associated 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 analyses and multiplex cytokine/chemokine assays from serum at baseline and at irAEs onset in melanoma 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 using single cell RNA sequencing. Multiplex immunohistochemistry and spatial transcriptomics on ICI-induced skin rash and colitis showed an increase in the proportion of CD4+ T-cells with IL-17A expression. Anti-IL-17A mAbs were administered in two patients with myocarditis, colitis and skin rash with resolution of the irAE. This study highlights the potential role of Type III CD4+ T-cells in irAEs development and provides proof-of-principle evidence for a corresponding clinical trial using anti-IL17A for treating irAEs. Code to generate the figures are located at https://github.com/pcheng84/AE_analysis/