DOP025Single-cell longitudinal profiling of peripheral blood identifies shared and therapy-specific immune signatures of early remission in ulcerative colitis

Abstract Background Patients with ulcerative colitis (UC) face a highly variable disease course, with only 10–20% achieving durable, long-term remission despite the availability of multiple biologic therapies. So far, limited insights exist into the immunological network states that determine whether a patient will respond to biologic treatment. Longitudinal single-cell RNA sequencing offers the opportunity to track dynamic cellular states and transcriptional programs over time, enabling the identification of early molecular signatures that distinguish responders from non-responders. Methods We performed longitudinal single-cell RNA-sequencing on PBMC samples from 32 ulcerative colitis patients treated with either anti-TNF, anti-IL12/23, anti-α4β7, or JAK inhibitors. The analysis included single-cell transcription profiles of PBMCs (2M cells) collected before and two and six weeks after the first round of treatments, with a subset (n = 10) including CITEseq. Salient patterns associated with overall or treatment-specific response were identified by determining shifts in immune cell proportions, differential expression in individual cell types and inferring strength of signalling networks using Cell Chat throughout the course of treatment. Differentially abundant changes were correlated with clinical remission at week 14 as a primary endpoint. Results Across treatments and regardless of responder state, we observed an early increased abundance of circulating conventional dendritic cells (cDCs). The increase in cDC type 2 cells was more pronounced in non-responders and showed a positive association with CRP, suggesting a link between DC2 dynamics and inadequate inflammatory control. Responders to anti-TNF and anti-α4β7 therapy mounted a strong interferon-response signature in CD14+ monocytes. This transcriptional shift was not observed with JAK inhibitors or anti-IL12/23 therapy. In anti-α4β7 patients, clinical remission was associated with early upregulation of Toll-like and NOD-like receptor signaling pathways in circulating myeloid cells, suggesting an innate immune activation state that remains sensitive to α4β7-mediated trafficking blockade in responders. Conclusion Our study reveals distinct early immune trajectories that differentiate effective from ineffective biologic therapy in UC. The identification of treatment-specific myeloid programs, particularly interferon-responsive monocyte states and maladaptive DC2 expansion, highlights immunological mechanisms that may drive individual therapeutic success of different MOAs. The findings provide a foundation for developing early, blood-based biomarkers capable of guiding personalized biologic selection and improving response prediction in UC. References: 1.Mishra N, et al. Longitudinal multi-omics analysis identifies early blood-based predictors of response to anti-TNF therapy. Genome Medicine. 2022. 2.Li Yim AYF, et al. An exploratory single-cell analysis of peripheral blood identifies T and myeloid cell differences associated with vedolizumab non-response. Frontiers in Immunology. 2025. 3.Thomas, T., Friedrich, M., Rich-Griffin, C. et al. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. Nat Immunol. 2024. Conflict of interest: P. Bernardes, Joana: I have no conflict of interest to declare Li Yim, Andrew: no conflict of interest Schulte-Schrepping, Jonas: no conflict of interest to declare Tran, Florian: Grant: Sanofi/Regeneron Personal Fees: Speaker’s fees: Abbvie, Bristol-Myers-Squibb, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, J & J, Sanofi, Takeda Consulting honoraria: AbbVie, J & J, Takeda Non-financial Support: Sanofi for statistical analysis Oldenburg, Lotte: none De Jonge, Wouter: no conflicts of interest Aden, Konrad: Personal Fees: Lecture fee: Takeda, Janssen, Lilly, Abbvie Consulting fee: Takeda, Jannsen, Lilly, Guidepoint D’Haens, Geert: Grant: Pfizer, BMS, Johnson and Johnson, Abbvie, Alimentiv BV, Eli Lilly, Takeda, Prometheus Laboratories Personal Fees: Abbvie, Abivax, Agomab, Alimentiv, Anaptys Bio, AstraZeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Glaxo Smith Kline, Dr Falk Pharma, Pfizer, Johnson and Johnson, Merck, Mirador, Polpharma, Procise Diagnostics, Prometheus Biosciences, Sorriso Pharma, Spyre, Takeda, Ventyx Vetrano, Stefania: no conflict of interest Schultze, Joachim L.: No conflict of interest to declare Schreiber, Stefan Wolfgang: Personal Fees: AbbVie, Alfasigma, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Rosenstiel, Philip: stock ownership Gerion