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bioRxiv · 10.1101/2021.08.15.456400

Hyperactive chemotaxis contributes to anti-TNFα treatment resistance in inflammatory bowel disease

Yau, T. O.·Vadakekolathu, J.·Foulds, G. A.·Du, G.·Polytarchou, C.·Dickins, B.·Rutella, S.
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Abstract

Background & AimsAnti-tumour necrosis factor-alpha (anti-TNF) agents have been used for inflammatory bowel disease (IBD), however, it has up to 30% non-response rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNF treatment are clearly needed. MethodsPublicly available transcriptomic data from IBD patients receiving anti-TNF therapy was systemically collected and integrated. In silico flow cytometry approaches and MetaScape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti-TNF-treated animal model (with lipopolysaccharide (LPS)-induced inflammation). The receiver operating characteristic (ROC) curve was applied to all genes to identify the best prediction biomarkers. ResultsA total of 449 samples were retrieved from control, baseline and after primary anti-TNF therapy or placebo. No statistically significant differences were observed between anti-TNF treatment responders and non-responders at baseline in immune microenvironment scores. Neutrophils, endothelial and B cell populations were higher in baseline non-responders and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly up-regulated in LPS-induced neutrophils but no statistically significant changes were observed in neutrophils treated with anti-TNF. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (ROC: 80.7%, 95% CI: 73.8% - 87.5%) with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in non-responders compared to responders (p < 0.0001). ConclusionsHyperactive chemotaxis influences responses to anti-TNF treatment and IL13RA2 is a potential biomarker to predict anti-TNF treatment response.

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Yau, T. O., Vadakekolathu, J., Foulds, G. A., Du, G., Polytarchou, C., Dickins, B., Rutella, S.. 2021-08-15. Hyperactive chemotaxis contributes to anti-TNFα treatment resistance in inflammatory bowel disease. https://doi.org/10.1101/2021.08.15.456400

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