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

• Published in: Nature communications Vol. 15; no. 1; pp. 1043 - 14
• Main Authors: Wiendl, Maximilian, Dedden, Mark, Liu, Li-Juan, Schweda, Anna, Paap, Eva-Maria, Ullrich, Karen A.-M., Hartmann, Leonie, Wieser, Luisa, Vitali, Francesco, Atreya, Imke, Müller, Tanja M., Günther, Claudia, Atreya, Raja, Neurath, Markus F., Zundler, Sebastian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 13/31; 38/91; 631/250/1619/554; 631/250/249/2510/1402; 631/80/84/2342; 692/4020/1503/257; 82/1; Antibodies; Cell activation; Crohn's disease; Cytotoxicity; E-cadherin; Flow cytometry; Humanities and Social Sciences; Inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Lymphocytes; Lymphocytes T; multidisciplinary; Science; Science (multidisciplinary); Stimulation; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45352-6

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 + β1 hi ) 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. The clinical success of anti- αEβ7 antibody Etrolizumab for Crohn’s disease is less than what is expected based on proof-of-concept studies. Here authors show, by characterization of T cells from Etrolizumab-treated patients, in vitro functional assays and reanalysis of public single cell datasets on Etrolizumab-treated patients, that at high level of T cell activation, which characterises T cells in Crohn’s disease, E-Cadherin-αEβ7 interactions become resistant to Etrolizumab inhibition.