A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Longitudinal Spatial Immune Profiling in Advanced Therapies: Enhancing Personalized Medicine for IBD

Chronic inflammatory bowel diseases are caused by an intestinal barrier disorder, increased translocation of bacteria into the intestinal wall, and a subsequent excessive inflammatory reaction. Despite significant advancements in treatment options in recent years, durable remission remains unattainable for a substantial proportion of patients. Currently, biomarkers capable of predicting therapeutic responses are lacking. According to current guidelines, available advanced therapies can be used with equal priority. To establish a logical sequence of therapies within the context of personalized medicine, it is important to understand how specific therapeutic agents modulate the disease at the cellular level. In this study, the authors investigated the immune landscape and the spatial organization of cells in the tissue at the single-cell level in patients with Crohn’s disease and ulcerative colitis before and after treatment with anti-tumor necrosis factor (anti-TNF) antibodies. Anti-TNF antibodies are still the most frequently used substance class when advanced therapy is needed. The authors generated approximately 1 million single-cell transcriptomes from 216 biopsies obtained from 41 individuals and identified 109 different cell types and states. This revealed both similarities and relevant differences between Crohn’s disease and ulcerative colitis. A comparison of patients who later achieved remission with those who did not respond to treatment with adalimumab revealed baseline differences in epithelial cells and myeloid cells. During therapy, certain cell profiles and cell interactions were associated with non-response to therapy, including increased interferon signaling in epithelial, immune, and stromal cells. In adalimumab-treated patients with rheumatoid arthritis, gene expression of the TNF signaling pathways and interferon signaling was found to be analogous to that in inflammatory bowel disease. This suggests shared pathological mechanisms across distinct immune-mediated diseases and indicates that Jak- or selective p19 inhibition may be useful after failure of anti-TNF therapy, as these modulate interferon signaling. Limiting factors for this study were the heterogeneous sampling time points during therapy (8 weeks to 1.5 years after the start of therapy), its sole focus on anti-TNF therapy effects, and the identification of inflammatory drivers at the RNA level, but not sufficiently at the protein level. Moreover, neutrophils, which play a central role in inflammatory bowel disease, were not captured in this dataset due to technical constraints. However, longitudinal profiling strategies such as these are crucial for understanding the dynamic development of immune-mediated diseases at the cellular level, thereby providing a foundation for selecting the most promising therapeutic agents and determining a logical sequence of treatments for individual patients. Moreover, such detailed analyses contribute to the identification of potential novel therapeutic targets.