T-Cell Subtypes and Immune Signatures in Cutaneous Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy

Simple Summary Immune-related adverse events (irAEs) as responses to immunotherapy are frequent and a burden to patients. While cutaneous irAEs (cutAEs) are a common side effect, some are linked to better overall survival and clinical responses to immunotherapy in patients. There are emerging reports on cutaneous side effects of immunotherapy; however, in-depth analysis of the underlying immunological signatures is rare. In this pilot study, we analyzed the T-cell signatures of cutAEs in melanoma patients undergoing immunotherapy and detected an evident shift towards a Th17-driven inflammatory profile. We identified distinct cytokine signatures specific for urticaria and T-cell-mediated cutAEs, as well as an increase in IL-10 in non-responders during cutAEs.Abstract Immune checkpoint inhibition (ICI) improves outcomes in melanoma patients, but associated T-cell activation frequently leads to immune-related cutaneous adverse events (cutAEs). To dynamically identify T-cell subtypes and immune signatures associated with cutAEs, a pilot study was performed in stage III-IV melanoma patients using blood samples for flow cytometry and cytokine analysis. Blood samples were taken from patients before initiation of ICI (naive), at the onset of a cutAE, and after 6 months of ICI treatment. Overall, 30 patients were treated either with anti-PD1 monotherapy or with anti-PD-1/anti-CTLA-4 combination therapy. Flow cytometry analysis of PBMCs showed that ICI induced an overall shift from a Th2 towards a Th1 profile. Twelve patients (40%) developed cutAEs, which were associated with increased Th22 cells and Th17 cells, supported by a tendency to have elevated Th17/Th22-associated cytokines such as IL-17A, IL-22 and IL-23 levels in the plasma. Cytokine signatures specific for urticaria and T-cell-mediated cutAEs were identified in the plasma of patients by a bead-based assay. IL-10 was elevated in non-responders and, interestingly, during cutAEs. In conclusion, we identified distinct immune signatures based on the Th17/Th22 pathway in cutAEs, both in PBMCs and plasma. In addition, our finding of upregulated IL-10 during cutAEs supports the notion of treating these patients early and adequately to avoid implications for the overall outcome.