DoCTIS: a single cell RNA-seq atlas of drug response to targeted therapies in immune-mediated inflammatory diseases

Introduction: Targeted therapies have revolutionized the management of immune-mediated inflammatory diseases (IMIDs), however, there is a substantial number of patients who respond poorly to a given drug. There is a big need to understand the factors that are associated with this heterogeneity.

Aims & Methods: The DoCTIS project (1) aims to characterize molecular variation both at the disease and drug response levels across six different

IMIDs. We applied single cell RNA sequencing to 360 peripheral blood mononuclear cell (PBMC) samples from 176 patients from six prevalent IMIDs –psoriasis (PS), psoriatic arthritis (PsA), Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)- treated with five different drugs targeting TNF, IL12p40, IL6R, BLySS, IL17 and JAK pathways. All patients were analyzed at two time points including baseline and at the week of clinical response creating an immune landscape of more than two million peripheral immune cells.

Results: We found large inter-disease differences both at the compositional and genetic regulatory programs. ScRNA-Seq analysis revealed large differences at the systemic level between the six IMIDs. Compositional analyses demonstrated that the circulating immune cell profiles of UC and CD were more similar to each other than to the rest of IMIDs, and also identified differences in pDC, MAIT, NK CD16- and T CD4+Memory subsets between both diseases. At the transcriptional level, we found the expected upregulated interferon response signature affecting multiple cell types in SLE, but also novel findings like strong regulatory differences in B and CD14+monocyte compartments between UC and CD, two diseases with a highly shared genetic risk. The impact of each drug was found to be largely disease-specific. Furthermore, we found multiple regulatory features associated with the effect of each drug as well the association to response.

Conclusion: The scRNA-Seq atlas developed in DoCTIS provides a unique resource for the understanding of drug response and disease heterogeneity across immune-mediated inflammatory diseases.

Informationen zum Einsatz von KI: -

 

Scroll to top

Publication History

Article published online:
04 September 2025