A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response
David Wu, Ashley Hailer, Sijia Wang, Michelle Yuan, Jamie S. Chan, Abdallah Kurdi, David Han, Hira Ali, H. Blaize D’Angio, Aaron T. Mayer, Maha K. Rahim, Ayano Kondo, Daniel M. Klufas, Esther Kim, A. Hunter Shain, Jaehyuk Choi, Tina Bhutani, Gregory L. Simpson, Roy C. Grekin, Roberto R. Ricardo-González, Elizabeth Purdom, Jeffrey P. North, Jeffrey B. Cheng, Raymond J. Cho
Abstract
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 and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.