Decoding the role of lipids in the metabolic control of CD8+ T cells by the gut microbiota to improve outcomes in colorectal cancer.
Worldwide Cancer Research
European Institute of Oncology
Over a third of resected early-stage colorectal cancer (CRC) relapse and patients die from metastatic disease. Infiltrating lymphocytes are independent positive predictor of survival in CRC, however only a small fraction of patients respond to immune checkpoint inhibitors (ICI). This project originates from two milestone discoveries. First, the gut microbiome modulates response to ICI, but the overlap across different cohorts is mostly functional rather than compositional. Second, accumulation of specific lipids in the tumor microenvironment (TME) impact the anti-tumor activity of CD8+ T cells. We have conducted comprehensive metagenomic, metabolomic and immune characterization on CRC patients, observing parallel changes in mucosa and tissues. Thus, we hypothesize that therapeutic manipulation of the metabolic output of mucosal bacteria can reshape the TME and improve the response of CRC to ICI. This prospective study is designed to: . DECODE the interplay between metabolic activities in the intestinal mucosa and immune cell functions on CRC patients; . VALIDATE the effect of lipids derived or induced by bacteria on immune cell functions; . TRANSLATE new knowledge into innovative strategies to improve ICI efficacy. Main objectives are: . Quantification of lipids and reconstruction of bacteria-host metabolic pathways, in tumours and surrounding tissues; . Characterization of the immunomodulatory impact of the microbiota on CD8+ T cells; . Mechanistic validation and improvement of ICI’s response on a novel patient-derived organ-on-chip device. This study will enable multi-scale profiling and predictive modelling on a fully annotated cohort while simultaneously spawning novel actionable targets for therapy. Tumour sensitivity to ICI will be tested, providing initial experimental validation on a patient-relevant and cost-effective system. Data generated through this project may also reconcile the limited association between the overall composition of the microbiome and the response to immunotherapy across different cohorts of patients, a crucial step toward new stratification strategies and therapeutic approaches.
2.1 Biological and endogenous factors