Our latest study reveals how colorectal cancer (CRC) tumors can directly shape the immune microenvironment by inducing a unique population of regulatory T (Treg) cells. Using a novel 3D organoid-T cell co-culture system, Sonia Aristin found that CRC tumor-derived organoids promote CD4+ T cell differentiation into a distinct, highly immunosuppressive Treg subset—without direct cell contact. These organoid-induced Tregs (TO-iTregs) have a unique transcriptional profile resembling tumor-infiltrating Tregs in CRC patients. Furthermore, high expression of TO-iTreg signature genes correlates with worse clinical outcomes in CRC. This model provides a new platform to explore immune regulation and develop strategies to disrupt tumor-induced immunosuppression.
Goodbye Enric!
After a decade in the Coffer Lab. senior scientist Enric Mocholi is heading back home to Valencia. Several generations of Coffers (2006-2024) joined to say goodbye. Enric has played an important role in the lab working on projects related to autophagy, metabolism and epigenetics, and co-supervising PhD students. We wish him success in setting up his own lab in Spain, and look forward to continued collaboration!
PhD survivor! Congratulations to Alessandro Cutilli
On October 17th, Alessnadro defended his PhD thesis titled: CD4+ and CD8+ behaviour in the landscape of intestinal damage: Prepare for trouble and make it double. Alessandro’s work investigated how CD4+ and CD8+ T lymphocytes behave during intestinal epithelial damage. Using co-cultures of human intestinal organoids and T cells, he examined chemotherapy's affect on intestinal cells and how this subsequently impacts T cell behaviour. Galectin-9 (Gal-9) was identified as a mediator that, when neutralized, reduces T cell proliferation and IFNγ production. Additionally he explored the effects of IFNγ-induced intestinal damage which was found to trigger the release of the chemokine CXCL11 promoting T cell migration. Finally Alessandro investigated T cell transcriptional repogramming in response to intestinal damage. These findings provide support for pre-clinical and prospective clinical investigations aimed at manipulating Gal-9 and CXCL11 to regulate T cell responses in the intestine.
You can learn more about Alessandro’s work if you click on the link here
Goodbye Cindy!
After 11 years in the Coffer Lab, Cindy Fredericks is leaving us to join Niels Eijkelkamp’s and Onno Krannenburg’s Labs. Cindy has played an essential role in the work of numerous PhD students and postdocs in the lab and she will be sorely missed. We wish her all the best with the new challenges!
Paper: How does interferon-mediated intestinal damage drive T cell recruitment?
Cytokines like interferon-gamma are key players in decisions driving inflammation and regeneration. Using a 3D co-culture model based on human intestinal organoids, PhD students Alessandro Cutilli and Suze Jansen discovered that interferon-gamma can reprogram the gut lining, leading it to express a set of pro-inflammatory genes. Specifically, they found an upregulation of chemokines CXCL9, CXCL10, and CXCL11—molecules that are key to recruiting immune cells. Their findings also showed that this reprogramming enhances T-cell migration, largely driven by CXCL11. These insights could open new therapeutic avenues: targeting CXCL11 might help prevent T-cells from trafficking to the inflamed intestine, potentially offering relief for conditions like inflammatory bowel disease (IBD). Check out the full study at:
https://pubmed.ncbi.nlm.nih.gov/39302156/
Paper: Chemotherapy induced intestinal damage directly modulates T cell behaviour
We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced intestinal epithelial cell (IEC) damage on T cell behavior. This has led to the identification of galactin-9 as playing an important role in driving CD4+ and CD8+ T cell responses. Congratulations to Suze Jansen and Alessandro Cutilli for all their work driving this study forward.
Highlights
Chemotherapy-induced intestinal epithelial damage can be modelled with organoids
3D-coculture model allows evaluation of epithelial damage on T cell homeostasis
Chemotherapy-induced epithelial damage modulates T cell activation and migration
Galectin-9 promotes T cell activation and migration in response to epithelial damage
Summary
The intestine is vulnerable to chemotherapy-induced damage due to the high rate of intestinal epithelial cell (IEC) proliferation. We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced IEC damage on T cell behavior. Exposure of intestinal organoids to busulfan, fludarabine, and clofarabine induced damage-related responses affecting both the capacity to regenerate and transcriptional reprogramming. In ex vivo co-culture assays, prior intestinal organoid damage resulted in increased T cell activation, proliferation, and migration. We identified galectin-9 (Gal-9) as a key molecule released by damaged organoids. The use of anti-Gal-9 blocking antibodies or CRISPR/Cas9-mediated Gal-9 knock-out prevented intestinal organoid damage-induced T cell proliferation, interferon-gamma release, and migration. Increased levels of Gal-9 were found early after HSCT chemotherapeutic conditioning in the plasma of patients who later developed acute GVHD. Taken together, chemotherapy-induced intestinal damage can influence T cell behavior in a Gal-9-dependent manner which may provide novel strategies for therapeutic intervention.
Welcome Claudia!
Cláudia Leite graduated in Biochemistry and holds a PhD in Molecular and Cell Biology from the University of Porto. During her PhD, she investigated how mitochondria adjusts their activity to regulate cell cycle progression in budding yeast. She has recently joined the Coffer lab as a postdoctoral researcher to investigate the role of nuclear acetyl-CoA-producing enzymes in regulating transcriptional reprograming.
