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 CD11c + HLA-DR + mononuclear phagocytes, CD64 bright CD163 − CD14 bright CD1c − CD1a ‒ inflammatory monocyte‒like cells were the predominant IL-23–producing cells and, together with CD64 − CD163 − CD14 − IL-23p19 − TNF-α + inflammatory dendritic cell‒like cells, were increased in lesional compared with those in nonlesional skin taken from the same patient. Within T cells, CD8 + CD49a + and/or CD103 + tissue-resident memory T cells, CD4 + CD25 + FoxP3 + regulatory T cells, and CD4 + CD49a − CD103 − T cells were increased. Moreover, CD4 + CD49a − CD103 − 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 CD4 + CD49a − CD103 − 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-17A + IL ‒ 17F + / – 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.