Systemic IL-23 blockade downregulates IL-23 receptor-expressing Type 17 T-cell subsets and upregulates regulatory gene expression in myeloid cells in human psoriasis skin

Recent single-cell studies indicated that IL-17-producing T-cells (T17) have diverse subsets expressing IL-17A, IL-17F, or a combination of them in human psoriasis skin. However, it is unknown how T17 subsets are differently regulated by IL-23 versus IL-17A blockades. Here, we studied 93 human psoriasis or control skin single-cell libraries from 42 subjects to understand how IL-23 versus IL-17A systemic blockades differently modify single-cell transcriptome of T17 cell subsets, dendritic cells/myeloid cells, and keratinocytes. Our study shows that IL-23 inhibition down-regulates IL-23 receptor-expressing pathogenic T17 subsets. In contrast, T17 cells expressing both IL-17A and IL-17F did not express the IL-23 receptor, and the percentage of this potentially non-pathogenic T17 subset increased after IL-23 inhibition. We also found out that the expression of the IL-17 negative regulation genes, such as TNFAIP3, increased in myeloid cells more after IL-23 inhibition than after IL-17A inhibition. These findings explain why the risk of candidiasis is not increased after IL-23 inhibition, unlike IL-17 inhibition, and the higher efficacy of IL-23 blockades for inducing psoriasis remission in the long term or suppressing relapses after stopping the injections compared to IL-17A blockades. In the anti-IL-23 monoclonal antibody (risankizumab) clinical trial (NCT04630652), psoriasis patients received risankizuamb 150 mg injections at baseline, month 1, and month 4 (3 injections). Pretreatment (PreTx) lesional (LS) and non-lesional (NL) skin biopsy tissues were harvested at baseline, and posttreatment (PostTx) LS biopsy tissue was harvested at month 7. Skin immune cells were isolated from the harvested skin tissues and analyzed by single-cell RNA sequencing (scRNA-seq) in integration with our previous single-cell libraries (GSE183047 and GSE151177) of control skin from healthy volunteers, psoriasis PreTx LS and NL, psoriasis PostTx LS (after) IL-17A inhibition. PostTx LS IL-17A inhibition single-cell libraries were generated from skin biopsy tissues harvested at month 3, after anti-IL-17A monoclonal antibody (secukinumab) 300 mg injections at baseline, week 1, week 2, week 3, week 4, and week 8 (6 injections). In total, we analyzed 93 human skin single-cell libraries (42 psoriasis PreTx LS, 25 psoriasis PreTx NL, 12 psoriasis IL-23 inhibition PostTx LS, 4 psoriasis IL-17A inhibition PostTx LS, and 10 control skin from healthy volunteers) from 42 subjects