A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.</p

Report from the Annual Meeting of Expert Group Chairs (WGCHAIRS)

The Annual Meeting of ICES Expert Group Chairs (WGCHAIRS) provides an opportunity for chairs of all ICES working groups to share experiences and ideas, co-ordinate work, meet with their steering group, Advisory Committee and Science Committee chairs, and highlight any support they need from the ICES network. The group also provides participants with updates on developments in the network and their implications, as well as opportunities to identify future science priorities and plans for advisory products. This 2023 meeting report contains advice-related, science-related and cross-cutting issues. The meeting in 2023 included an extra day for incoming chairs, covering an introduction on the responsibilities for chairs, an introduction to the guidelines for ICES groups and a forum to express expectations and ask questions for the Chairs of the Advisory and Science Committees. The advice topics that were addressed include conservation aspects in advice, challenges and solutions for advice-based working groups, guidelines for Benchmarks, exploring reference points, the Transparent Assessment Framework (TAF), online advice, and the Workplan for 2023. The science topics that were addressed include how we can make ICES science more visible, implementing the Science Plan, the next steps for the Ecosystem-Based Management (EBM) Framework, and breakout groups for steering group chair interaction. Cross-cutting topics included an update on the action items from the WGCHAIRS meeting 2022, gender and inclusivity in ICES, the Code of Ethics and Professional Conduct, developing and implementing methods for the knowledge that flows into advice, ICES Publications and the new ICES library, update from Overviews including the data profiling tool and pipeline, and a presentation and exercise on the role of scientists in ICES, as an applied science organisation Key actions resulting from the meeting are: The Secretariat, ACOM and SCICOM chairs develop an outline for chairs’ training in dialogue with chairs. An additional meeting in 2023 is needed to discuss the future and next steps on Diversity, Equity, and Inclusion (DEI) implementation together with WGCHAIRS. Secretariat, ACOM and SCICOM to work on a communication strategy: what is a feasible and meaningful way of communication and how can we use it most efficiently are the main questions. Communication needs to be focused, separating the signal from the noise. What kind of impact does ICES want to make, and who are the target groups

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH -Mutant Molecular Profiles

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance

SINGLE CELL RNA SEQUENCING OF ULCERATIVE COLITIS AND CROHN'S DISEASE TISSUE SAMPLES INFORMS THE SELECTION OF TREM1 AS A TARGET FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASES

Abstract Ulcerative colitis (UC) and Crohn’s disease (CD) are complex and heterogenous diseases characterized by chronic and 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. In this study, 41 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 from multiple anatomic locations 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. Differential cell composition and gene expression analysis of the single cell data revealed inflammatory monocyte subtypes as highly enriched in inflamed relative to uninflamed samples, and 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. 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, with inhibition of TREM1 signaling expected to address pathology while maintaining an anti-bacterial response. 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. Figure 1. tSNE plot of myeloid cells from inflamed IBD tissue samples demonstrating high TREM1 expression across inflammatory monocytes</jats:p

Bidirectional histone monoaminylation dynamics regulate neural rhythmicity

Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles in permissive gene expression 1, 2–3. We previously demonstrated that serotonylation 4, 5, 6, 7, 8, 9–10 and dopaminylation 9,11, 12–13 of Gln5 of histone H3 (H3Q5ser and H3Q5dop, respectively) are catalysed by transglutaminase 2 (TG2), and alter both local and global chromatin states. Here we found that TG2 additionally functions as an eraser and exchanger of H3 monoaminylations, including H3Q5 histaminylation (H3Q5his), which displays diurnally rhythmic expression in brain and contributes to circadian gene expression and behaviour. We found that H3Q5his, in contrast to H3Q5ser, inhibits the binding of WDR5, a core member of histone H3 Lys4 (H3K4) methyltransferase complexes, thereby antagonizing methyltransferase activities on H3K4. Taken together, these data elucidate a mechanism through which a single chromatin regulatory enzyme has the ability to sense chemical microenvironments to affect the epigenetic states of cells, the dynamics of which have critical roles in the regulation of neural rhythmicity.</p

Molecular characterization of colorectal cancer related peritoneal metastatic disease

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity

Molecular characterization of colorectal cancer related peritoneal metastatic disease

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity