Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells.
Maximilian WiendlMark DeddenLi-Juan LiuAnna SchwedaEva-Maria PaapKaren Anne-Marie UllrichLeonie HartmannLuisa WieserFrancesco VitaliImke AtreyaTanja M MüllerClaudia GüntherGisela FeltenMarkus Friedrich NeurathSebastian ZundlerPublished in: Nature communications (2024)
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.
Keyphrases
- phase iii
- open label
- clinical trial
- phase ii
- double blind
- placebo controlled
- nk cells
- induced apoptosis
- cell migration
- poor prognosis
- gene expression
- big data
- study protocol
- machine learning
- randomized controlled trial
- cell therapy
- dna methylation
- genome wide
- cell death
- mesenchymal stem cells
- bone marrow
- human health
- signaling pathway