P0104 Decoding cytokine networks in ulcerative colitis to identify pathogenic mechanisms and therapeutic targets

Abstract Background Cytokines are key signalling molecules of the immune system that play critical roles in immune regulation. Cytokine ligands binding to their receptors initialise signalling cascades, culminating in the regulation of downstream target genes, including other cytokines. Thus, cytokines can form complex networks of interactions, in which cytokines regulate the production and activity of other cytokines, thereby organising immune responses. Such cytokine–cytokine interactions are important for maintaining the proper balance and specificity of immune responses. However, when dysregulated, chronic immune-mediated inflammatory disorders such as ulcerative colitis (UC) can develop. Despite the advent of advanced therapies targeting cytokine signalling, treatment outcomes for UC patients remain suboptimal. As such, there is a pressing need to better understand the cytokine regulation in UC by comprehensively mapping the interconnected cytokine signalling networks perturbed in UC patients. Methods We undertook single-cell systems immunology modelling of colonic biopsies of treatment-naive and treatment-exposed UC patients and healthy controls using harmonised single-cell transcriptomics data from the scIBD atlas [1]. This dataset allowed us to build condition specific cytokine signalling networks underpinned by putative cytokine–cytokine interactions. Results The generated cytokine networks effectively captured known physiologically relevant cytokine–cytokine interactions, which we recapitulated in vitro using UC patient-derived colonic epithelial organoids (n = 4). The resulting cytokine networks revealed new aspects of UC pathogenesis, including a cytokine subnetwork unique to treatment-naive UC patients. We identified highly rewired cytokines across UC disease states (TL1A, IL22, IL23A, and OSM), and JAK paralogue-specific cytokine–cytokine interactions that may inform the broader cytokine network effects of JAK inhibitor treatment. The cytokine network captures all significantly downregulated cytokine targets of anti-TL1A treatment shown in Hassan-Zahraee et al. [2], highlighting TL1A as an important upstream regulator of TNF and IL23A. Conclusion These findings open up novel avenues for guiding future cytokine-targeting therapeutic approaches in UC, by highlighting the likely downstream cytokines perturbed by cytokine inhibition, and elucidating the cytokine signalling differences in treatment-naive and treatment exposed UC. The presented methodology [3] can be readily applied to gain similar insights into other immune-mediated inflammatory diseases (IMIDs). References [1]:Nie H, Lin P, Zhang Y, Wan Y, Li J, Yin C, Zhang L. Single-cell meta-analysis of inflammatory bowel disease with scIBD. Nature Computational Science. 2023 Jun;3(6):522-531. doi: 10.1038/s43588-023-00464-9. Epub 2023 Jun 15. PMID: 38177426. [2]:Hassan-Zahraee M, Ye Z, Xi L, Baniecki ML, Li X, Hyde CL, Zhang J, Raha N, Karlsson F, Quan J, Ziemek D, Neelakantan S, Lepsy C, Allegretti JR, Romatowski J, Scherl EJ, Klopocka M, Danese S, Chandra DE, Schoenbeck U, Vincent MS, Longman R, Hung KE. Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis. Inflammatory Bowel Diseases. 2022 Mar 2;28(3):434-446. doi: 10.1093/ibd/izab193. PMID: 34427649; PMCID: PMC8889296. [3]:Olbei M, Hautefort I, Thomas JP, Csabai L, Bohar B, Ibraheim H, Saifuddin A, Modos D, Powell N, Korcsmaros T. Decoding Cytokine Networks in Ulcerative Colitis to Identify Pathogenic Mechanisms and Therapeutic Targets. bioRxiv 2024.09.12.612623; doi: https://doi.org/10.1101/2024.09.12.612623