Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells

Wiendl M, Dedden M, Liu L, Schweda A, Paap EM, Ullrich K, Hartmann L, Wieser L, Vitali F, Atreya I, Müller T, Günther C, Atreya R, Neurath M, Zundler S (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 15

Article Number: 1043

Journal Issue: 1

DOI: 10.1038/s41467-024-45352-6

Abstract

Despite promising preclinical and earlier clinical data, a recent phase III trial on the anti-β7 integrin antibody etrolizumab in Crohn’s disease (CD) did not reach its primary endpoint. The mechanisms leading to this outcome are not well understood. Here we characterize the β7+ T cell compartment from patients with CD in comparison to cells from individuals without inflammatory bowel disease. By flow cytometric, transcriptomic and functional profiling of circulating T cells, we find that triple-integrin-expressing (α4+β7+β1hi) T cells have the potential to home to the gut despite α4β7 blockade and have a specific cytotoxic signature. A subset of triple-integrin-expressing cells readily acquires αE expression and could be co-stimulated via E-Cadherin-αEβ7 interactions in vitro. Etrolizumab-s fails to block such αEβ7 signalling at high levels of T cell stimulation. Consistently, in CD patients treated with etrolizumab, T cell activation correlates with cytotoxic signatures. Collectively, our findings might add one important piece to the puzzle to explain phase III trial results with etrolizumab, while they also highlight that αEβ7 remains an interesting target for future therapeutic approaches in inflammatory bowel disease.

Authors with CRIS profile

Maximilian Wiendl Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Mark Dedden Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Lijuan Liu Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Eva-Maria Paap Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Karen Ullrich Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Leonie Wittner Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Luisa Wieser Lehrstuhl für Innere Medizin I Francesco Vitali Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Imke Atreya Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Tanja Müller Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Claudia Günther Professur für Gastrointestinale Pathophysiologie Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Markus Neurath Lehrstuhl für Innere Medizin I Sebastian Zundler Professur für Immunzellmigration TT (Else Kröner Clinican Scientist-Professur)

How to cite

APA:

Wiendl, M., Dedden, M., Liu, L., Schweda, A., Paap, E.-M., Ullrich, K.,... Zundler, S. (2024). Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-45352-6

MLA:

Wiendl, Maximilian, et al. "Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells." Nature Communications 15.1 (2024).

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