Project Details
Projekt
Gut bacteria-derived metabolites as modulators of tumour intrinsic immunogenicity in colorectal cancer liver metastases
Applicants
Dr. Conrad Rauber; Maria Paula Roberti, Ph.D.
Subject Area
Gastroenterology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 537604907
Patients with microsatellite stable-colorectal cancers (MSS-CRC) are considered resistant to immune checkpoint blockade (ICI) treatment. Previously, we have demonstrated in preclinical models that response of MSS-CRC to ICI (in combination with chemotherapy) depends on intestinal microbiota and is mediated by systemic effects on the immune system. Based on these findings, MSS-CRC tumours may be rendered susceptible to anti-PD1 therapy by a selected combination of a platinum-based compound, anti-PD-1 antibodies and gut immunogenic bacteria. Furthermore, we recently demonstrated that ketone body and bile acid metabolism also impacted therapy response in tumours. Based on these findings, we hypothesise that gut microbiota-derived metabolites in the blood can impact distant metastasis by altering tumour intrinsic gene expression pathways that determine tumour immunogenicity thus altering tumour immunosurveillance and response to treatment. To test this hypothesis, we will characterise gut-microbiota metabolites in CRC samples (from GenomiCC biobanks), then apply our high throughput immunoprofiling platform in CRC cell lines and PDOs to identify and characterize microbiota-derived metabolites that modulate tumour intrinsic pathways of immune recognition. Finally, potential candidates will be tested in murine orthotopic CRC metastasis models to identify metabolites that can sensitise MSS-CRC tumours to immunotherapies.
DFG Programme
Research Units
