DOP02 Single cell RNA sequencing of Ulcerative Colitis and Crohn's Disease tissue samples informs the selection of Triggering Receptors Expressed on Myeloid Cells 1 (TREM1) as a target for the treatment of Inflammatory Bowel Diseases
Grant, S.(1)*;Johnson, K.(1);Thomas, T.(2);Honig, G.(1);Bielecki, P.(1);Dendrou, C.(3);Guo, S.(1);Kulicke, R.(1);Li, P.(1);L'Italien, L.(1);Spies, N.(1);Stransky, N.(1);Uhlig, H.(4);Varma, M.(1);Travis, S.(5);Buckley, C.(2);Magram, J.(1);
(1)Celsius Therapeutics, Research and Development, Cambridge MA, United States;(2)Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom;(3)Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;(4)Translational Gastroenterology Unit and Department of Pediatrics, University of Oxford, Oxford, United Kingdom;(5)Kennedy Institute and Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom;
Background
Ulcerative colitis (UC) and Crohn’s disease (CD) are complex and heterogenous diseases characterized by chronic, progressive inflammation of the digestive tract. Single cell RNA sequencing combined with computational biology provides unprecedented insights into disease biology, informing novel therapeutic targets and precision medicine approaches. To identify potential mediators of persistent inflammation in inflammatory bowel disease (IBD), we performed single cell RNA sequencing on tissue samples collected from UC and CD patients before and after beginning adalimumab.
Methods
Forty-one participants, including 21 UC patients, 17 CD patients and 3 healthy individuals, were enrolled at the University of Oxford’s Translational Gastroenterology Unit and Kennedy Institute of Rheumatology. Patients had moderate-to-severe disease based on symptoms and endoscopy, were biologic naïve, and planned to initiate adalimumab. Mucosal biopsies for single cell RNA sequencing were collected for each subject before beginning and after a minimum of 3 months of adalimumab, at which time treatment response was assessed. During the study, clinical response as defined by composite measures was observed in 8 UC and 9 CD patients.
Results
Differential cell composition and gene expression analysis of single cell data revealed inflammatory monocyte subtypes as highly enriched in inflamed relative to uninflamed samples. This cellular subset remained highly elevated in inflamed samples from adalimumab non-responders. These cells were characterized by expression of multiple cell-surface receptors with potential to drive pathology, including TREM1 (Triggering Receptor Expressed on Myeloid Cells 1), a transmembrane receptor that amplifies anti-bacterial neutrophil and monocyte mediated responses. TREM1+ inflammatory monocytes were highly enriched in UC and CD inflamed samples (Fig. 1), both prior to adalimumab and in adalimumab non-responders. The enrichment of TREM1+ cells was specific to inflamed IBD tissue and was not observed in non-inflamed tissue from IBD patients or healthy subjects; enrichment of TREM1+ cells was also not observed in circulating peripheral blood mononuclear cells.
Conclusion
TREM1+ neutrophils and monocytes in the gut mucosa amplify innate immune responses to bacteria in the context of epithelial barrier dysfunction and bacterial dysbiosis in IBD. When activated, TREM1 signaling induces multiple soluble mediators relevant for IBD pathology. Our single cell RNA sequencing data provide further evidence that TREM1 is an exciting therapeutic target for UC and CD. We therefore developed a highly potent and selective monoclonal antibody inhibitor of TREM-1, CEL383, with the Phase 1 clinical trial expected to start in 2023.