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

Yau, T.O. ORCID: 0000-0002-3283-0370, Vadakekolathu, J. ORCID: 0000-0002-2671-4285, Foulds, G.A. ORCID: 0000-0002-2053-7580, Du, G., Dickins, B. ORCID: 0000-0002-0866-6232, Polytarchou, C. ORCID: 0000-0002-1948-7934 and Rutella, S. ORCID: 0000-0003-1970-7375, 2021. Hyperactive neutrophil chemotaxis contributes to anti‐TNFα treatment resistance in inflammatory bowel disease. Journal of Gastroenterology and Hepatology. ISSN 0815-9319

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Abstract

Background & aims: Anti-tumour necrosis factor-alpha (anti-TNFα) 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-TNFα treatment are needed.

Methods: Publicly available transcriptomic data from IBD patients receiving anti-TNFα 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-TNFα-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.

Results: A total of 449 samples were retrieved from control, baseline and after primary anti-TNFα therapy or placebo. No statistically significant differences were observed between anti-TNFα 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-TNFα. 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).

Conclusions: Hyperactive neutrophil chemotaxis influences responses to anti-TNFα treatment, and IL13RA2 is a potential biomarker to predict anti-TNFα treatment response.

Item Type: Journal article
Publication Title: Journal of Gastroenterology and Hepatology
Creators: Yau, T.O., Vadakekolathu, J., Foulds, G.A., Du, G., Dickins, B., Polytarchou, C. and Rutella, S.
Publisher: Wiley
Date: 20 December 2021
ISSN: 0815-9319
Identifiers:
NumberType
10.1111/jgh.15764DOI
1505127Other
Rights: This is the peer reviewed version of the following article: Yau, T. O., Vadakekolathu, J., Foulds, G. A., Du, G., Dickins, B., Polytarchou, C., & Rutella, S. (2021). Hyperactive neutrophil chemotaxis contributes to anti‐TNFα treatment resistance in inflammatory bowel disease. Journal of Gastroenterology and Hepatology, which has been published in final form at https://doi.org/10.1111/jgh.15764. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
Divisions: Schools > School of Science and Technology
Record created by: Laura Ward
Date Added: 10 Jan 2022 09:11
Last Modified: 10 Jan 2022 09:11
URI: http://irep.ntu.ac.uk/id/eprint/45196

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