Established Researcher Swiss Federal Institute of Technology Zurich Basel, Switzerland
Disclosure(s):
Xenia Ficht, PhD: No financial relationships to disclose
Introduction/Rationale: Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal tract affecting millions worldwide. TNF-α–blocking antibodies are widely used to control inflammation and induce remission; however, more than half of patients either fail to respond initially or develop secondary loss of response. While anti-drug antibodies (ADA) account for a subset of cases, some patients develop treatment resistance through mechanisms that remain poorly understood and cannot be overcome by dose escalation.
Methods: To investigate these mechanisms, we assembled a cohort of archival intestinal biopsies from patients with either ADA-negative secondary loss of response or sustained response to TNF-α inhibitors. Samples were incorporated into tissue microarrays and analyzed using Xenium spatial transcriptomics with a customized panel of intestinal and inflammation-associated genes. The same tissue sections were subsequently profiled by high-plex immunofluorescence using PhenoCycler staining with a panel of over 20 markers.
Results: Integrated spatial transcriptomic and proteomic analyses identified inflammation-associated cell populations and molecular pathways linked to secondary loss of response in the ileum and colon.
Conclusion: These signatures suggest pharmacodynamic mechanisms underlying ADA-negative treatment failure and highlight candidate prognostic biomarkers for future loss of response.
