Abstract The development of inhibitory agents against interleukin 23 (Ustekinumab and Risankizumab) has significantly advanced therapies for Crohn’s Disease (CD). The immune and epithelial compartments are potent targets of IL-23 biologics. Nevertheless, the mechanistic insights provided have yet to be fully translated into clinical practice. Recently, studies reported CD8+ T-cells as non-classical IL-23 responders, pointing to a previously underappreciated role of these cells in IL23-driven inflammation. Such findings primarily emerge from models and/or patients with colitis, with limited exploration in the ileitis context. To dissect the role of CD8+ T-cells in IL23-driven CD, we employed the TnfΔARE mouse, a CD8+ T cell-dependent model of CD-like ileitis. Conditional Il23r deletion from CD8+ T-cells (Il23rCD8KOTnfΔARE) conferred substantial amelioration of inflammation in vivo, intriguingly restricted to female mice, resembling clinical observations of poor male sex response to Ustekinumab. This effect was dependent on female sex hormones, as assessed through ovariectomy experiments. Bulk RNA sequencing on total CD8+ T-cells of control and Il23rCD8KOTnfΔARE mice revealed significant alterations limited to female cells that associated with sustained proliferative and metabolic activity. Single cell RNA-sequencing (scRNA-seq) defined specific subtypes as potential IL23 responders in the TnfΔARE ileum, which exhibited strong transcriptional alterations upon inflammation and significantly expanded in diseased tissue. Cross-species comparison with a human Ulcerative Colitis (UC) dataset confirmed conserved Il23r-driven cell responses. The combination of bulk and scRNA-seq data further enabled us to preclinically identify a set of biomarkers, whose potency is under investigation. The proposed association of sex with anti-IL23 treatment in IBD is currently assessed in a real world setting of CD patients. Our retrospective evaluation of Ustekinumab-treated patients so far indicates better response rates in females, particularly in biologic-experienced and surgery-naïve subjects. These findings highlight a novel, sex-dependent mechanism of IL-23 in CD8+ T-cells offering insights into more precise patient stratification for anti-IL23 therapy and valuable implications for personalized IBD treatment.
Iliopoulou et al. (Thu,) studied this question.