1544 Disruption of a pathologic, skin-resident T17 cell identity in clinically effective IL23 blockade of psoriasis

Psoriasis vulgaris and certain other chronic inflammatory diseases improve markedly with biologic blockade of IL23 signaling in T cells, but 10-20% of patients demonstrate drug insensitivity. The genetic mechanisms of this therapeutic resistance remain poorly understood. We single-cell transcriptomically and spatially profiled CD45+ immune cells isolated from lesional psoriatic skin of 9 patients before and after treatment with tildrakizumab, a monoclonal antibody antagonizing IL23. In all clinically responsive patients, an abnormal transcriptional signature in skin-resident memory T17 cells was normalized (individual patient Wilcoxon p < 0.001 for all responders). In contrast, non-responsive patients showed distinct causes of drug insensitivity, including persistent pathogenic T17 cell activation, a mechanism distinct from alternative cytokine signaling or downstream resistance. Blockade also dampens interferon-related antigen presentation programs in psoriatic macrophages and mast cells. However, a subset of disease-specific T17 abnormalities persists even in responsive patients, suggesting an irreversible cell identity necessitating ongoing IL23 inhibition. Spatial transcriptomic analysis further revealed programmatic keratinocyte responses to infiltrating lymphocytes, indicating that resistant disease is maintained by as little as 9% residual IL17-induced signaling (responders vs non-responders Wilcoxon p < 0.001). Collectively, our data establishes a molecular paradigm for dissecting patient-level responses to immunomodulatory treatment.