A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma
Florentia Dimitriou, Phil F. Cheng, Annalisa Saltari, Katrin Schaper‐Gerhardt, Ramon Staeger, Veronika Haunerdinger, Federica Sella, Aizhan Tastanova, Christian Urban, Susanne Dettwiler, Daniela Mihic‐Probst, Christian M. Matter, Olivier Michielin, Ralf Gutzmer, Georgina V. Long, Burkhard Becher, Mitchell P. Levesque, Reinhard Dummer
Abstract
Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4+ T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4+ T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4+ T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events. Dimitriou et al. perform multiomic profiling of patients with melanoma experiencing immunotherapy-associated toxicity and identify a targetable role for type III-associated immune responses with an increase in CD4+ T cells expressing IL-17A.