Track: Clinical Studies

Topic: Inflammatory Diseases

Abstract:

Psoriasiform toxicity comprises up to 4% of cutaneous immune-related adverse events (irAEs) seen in patients with immune checkpoint inhibitor therapy. Most psoriasiform irAEs are mild, however, ~10% of patients develop severe reactions including pustular psoriasis or erythroderma, and 50% of patients require interruption or discontinuation of immunotherapy. A few reported psoriasiform irAE cases have highlighted therapeutic benefits when treated with biologic agents designed for de novo psoriasis; however, little is known about the underlying immunopathogenesis of psoriasiform irAEs and how this varies from de novo psoriasis. In this study, we profiled psoriasiform irAE (n=5) and de novo psoriasis (n=5) biopsy samples using the next-generation sequencing HTG EdgeSeq Precision Immuno-Oncology Panel assessing mRNA expression of >1390 genes. We used an FDR of <0.05 and a Log₂fold-change of >1.0 to identify significantly altered genes. Unsupervised clustering analysis identified two distinct patterns for upregulated and downregulated genes, with one cluster containing all five psoriasiform irAE samples and the other containing all five de novo psoriasis samples. Psoriasiform irAE samples had 17 upregulated genes including the noncanonical regulatory T-cell marker FOXA1, keratin-19, and components of the interleukin-17 (IL17) signaling pathway. There were 16 downregulated genes including IL1B, IL20, and chemokine C-X-C ligand 8 (CXCL8). We found global downregulation of genes involved in tumor necrosis factor-α (TNFα) signaling in psoriasiform irAE samples. These data suggest that differential upregulation of cytokine signaling pathways may be responsible for immunotherapy-related psoriasiform reactions versus de novo psoriasis. Additional studies are required to elucidate the mechanism of these cutaneous irAEs further.

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Ganiraju Manyam, PhD