P167 Remodelling of the colonic molecular landscape in patients failing anti-TNF therapy highlights dysregulation of the extracellular matrix in ulcerative colitis

Abstract

Abstract Background In patients with ulcerative colitis (UC) who previously failed anti-TNF therapy, subsequent treatment with other advanced therapies is generally less effective than they are in anti-TNF naïve patients. Since anti-TNF drugs are frequently used first-line in UC, drug sequencing depreciation poses a major clinical challenge. To understand potential underlying mechanisms, we compared the clinical and molecular phenotype of UC patients who failed anti-TNF therapy with those who were anti-TNF naïve. Methods Clinical information and mucosal gene expression profiles were collected from 262 anti-TNF naïve and 275 anti-TNF exposed individuals with moderate to severe UC enrolled in the UNIFI clinical trial programme. We assessed differences between the groups in terms of clinical parameters, gene expression levels, pathway and transcription factor activity, as well as cellular composition. Results Anti-TNF exposed patients had significantly increased disease duration (p=0. 000009), CRP (p=0.03), and histological severity[PN1] (p=0.002). After adjusting for these factors, we identified 1,592 genes differentially expressed (FDR < 0.05), although the expression changes were quite modest. Pathway analysis linked previous anti-TNF exposure to significant downregulation of TNF and NFkB signalling and up-regulation of extracellular matrix components, stroma-related signatures, and growth factor receptor (EGFR, MAPK, PI3K) and TGFb signalling. These data were in line with results from cellular deconvolution methods, which showed an increase in stromal cell abundance and T cell depletion following anti-TNF failure. Gene regulatory network inference suggested that the observed gene expression differences were driven by increased activity of many transcriptional regulators, including those downstream of RUNX1 and RUNX3. Conclusion In patients with active UC, prior anti-TNF failure is associated with molecular remodelling of the colon characterised by dysregulated ECM organisation and shifts in stromal compartments. These data provide new insights into potential mechanisms of drug sequencing depreciation and could inform novel strategies to overcome this challenging clinical phenomenon.