A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response

• DOI: 10.1126/sciimmunol.adi2848
• Publication Date: 2024-01-26T18:59:11Z
• Authors: David Wu; Ashley A. Hailer; Sijia Wang; Michelle Yuan; Jamie Chan; Abdullah El Kurdi; David Han; Hira Ali; Blaize D’Angio; Aaron Mayer; Maha Rahim; Ayano Kondo; Daniel Klufas; Esther Kim; A. Hunter Shain; Jaehyuk Choi; Tina Bhutani; Gregory Simpson; Roy C. Grekin; Roberto Ricardo-G...; Elizabeth Purdom; Jeffrey P. North; Jeffrey B. Cheng; Raymond J. Cho
• Keywords: Interleukin-23

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before during IL-23 blockade. In clinically responsive patients, a transcriptional signature in skin-resident memory T was strongly attenuated. contrast, patients were distinguished by persistent activation IL-17–producing (T17) cells, mechanism distinct alternative cytokine signaling or resistance to epidermal keratinocytes. Even blockade–responsive detected recurring set recalcitrant, disease-specific abnormalities. This irreversible immunological state may necessitate ongoing inhibition. Spatial transcriptomic analyses also suggested that successful requires dampening >90% IL-17–induced response lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish patient-level paradigm for dissecting immunomodulatory treatments.