Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab.

Cellular sources of IL-23 and IL-17A driving skin inflammation in psoriasis remain unclear. Using high-dimensional unsupervised flow cytometry analysis, mononuclear phagocytes and T cells were examined in the same lesions of patients before and during guselkumab (IL-23p19 blocker) or secukinumab (IL-17A blocker) treatment. Among CD11cHLA-DR mononuclear phagocytes, CD64CD163CD14CD1cCD1a inflammatory monocyte‒like cells were the predominant IL-23-producing cells and, together with CD64CD163CD14IL-23p19TNF-α inflammatory dendritic cell‒like cells, were increased in lesional compared with those in nonlesional skin taken from the same patient. Within T cells, CD8CD49a and/or CD103 tissue-resident memory T cells, CD4CD25FoxP3 regulatory T cells, and CD4CD49aCD103 T cells were increased. Moreover, CD4CD49aCD103 T cells and the relatively rare CD8 memory T cells equally contributed to IL-17A production. Both treatments decreased the frequencies of inflammatory monocyte‒like, inflammatory dendritic cell‒like, and CD4CD49aCD103 T cells. In contrast, guselkumab reduced memory T cells while maintaining regulatory T cells and vice versa for secukinumab. Neither drug modified the frequencies of IL-17AIL17F/ CD4 or CD8 T cells. This study reveals the identity of the major IL-23 mononuclear phagocyte and IL-17 T-cell subsets in psoriatic skin lesions and paves the way for a better understanding of the mode of action of drugs targeting the IL-23/IL-17A pathway in psoriasis.