Characterization of the gut mucosa transcriptome in extraintestinal cancer and ICI-responders & Development of a gut mucosa-based biomarker score to predict response to gut microbiome-based interventions

• Applicants: Dr. Conrad Rauber; Maria Paula Roberti, Ph.D.
• Subject Area: Gastroenterology ; Hematology, Oncology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537739196

In recent years, the link between the gut microbiome and a variety of human diseases has been increasingly recognized. In extraintestinal tumor diseases, we have shown in the past that the response to tumor immunotherapy (e.g. PD-1 blockade or CTLA-4 blockade) depends significantly on the composition of the patient's gut microbiome and sensitive to antibiotic perturbations. However, the gut microbiome composition is dependent on many external factors and gut microbiota biomarkers have not been reproducible among different clinical cohorts. Gut mucosal tissue is where the physiological and immune changes resulting from the microbiota activity are primarily imprinted, therefore we postulate mucosal biomarkers to have a stronger prognostic/predictive value. In the study presented here, we aim to investigate the gene expression profile (transcriptome) of the intestinal mucosa in different intestinal regions. For this purpose, patients with and without tumor will have a mucosal sample taken during colonoscopy from the terminal ileum as well as from the ascending and descending colon. In these tissue samples, we will determine gene activation (transcriptome of the intestinal mucosa) and the profile of mucosal bacteria and compare them among the groups. The mucosal gene expression signatures will determine a "MucoScore". We hope to find differences between healthy patients, patients with tumors before therapy and those who have responded particularly well to immunotherapy. The MucoScore is then compared with the mucosal and fecal microbiota composition to test which potential biomarker is stronger. The cause-effect of the gut microbiota dictating the MucoScore and impacting on responses to immunotherapy will be proven in experimental murine models. We hope to find a temporally stable marker for intestinal immune health with the intestinal mucosa and ist MucoScore, which can be used in early clinical trials. Furthermore, we want to identify patients who are at high risk of not responding to tumor immunotherapies due to an unfavorable MucoScore, in order to then treat them with safe and constantly available stool samples from healthy subjects to improve response.

• DFG Programme: Research Grants