Cellular cartography: characterizing tissue immune landscapes in IBD and cancer

1. RasGRP1 Regulation in Autoimmunity
T cell selection is essential to allow maturation only of capable and not auto-reactive T cells.
Our research demonstrates that reduced expression of RasGRP1 (a key factor in T cell receptor signaling) leads to defects in T cell selection and autoimmunity in mice.
Reduced expression of RasGRP1 was observed in T cells of patients with rheumatoid arthritis, with a more pronounced reduction in active disease.
We identified a regulatory mechanism of RasGRP1 expression where the transcription factor RUNX1 interacts with an enhancer region containing SNPs associated with autoimmunity.
RUNX1 was found to be less expressed in T cells of patients with rheumatoid arthritis as well, suggesting involvement in RasGRP1 regulation and autoimmunity.

2. Improved Single-Cell Segmentation for Imaging Mass Cytometry data
We developed a novel method called MATISSE to improve the segmentation quality of single cells in tissue images captured using a multiplex technology called Imaging Mass Cytometry (IMC).
We apply a fluorescence microscopy step preceding IMC imaging, boosting the identification of individual cell nuclei at higher resolution.
This vastly reduces cell segmentation artifacts such as merged and fragmented events.
With this approach, more complete and reliable single-cell datasets can be generated, which is essential to study tissue biology.

3. Inflammatory Bowel Disease & Colitis-Associated Cancer
Long-standing active inflammatory bowel disease (IBD) increases risk of developing colorectal cancer, specifically colitis associated cancer (CAC).
We apply several technologies, including IMC to characterize the immune context of CAC development in uninflamed, inflamed, and early dysplastic samples of IBD patients.
Key findings include a robust increased type 3 inflammation (IL-17) and JAK-STAT signaling (P-STAT3) in inflamed and early dysplastic tissue, while cytotoxic T cell surveillance of epithelial cells appears reduced compared to the uninflamed condition.

4. Colorectal Cancer Metastasis
We investigated the tumor microenvironment in high microsatellite instability (MSI-H) colorectal primary tumors in the context of metastatic capacity.
By means of multiplex tissue imaging we revealed distinct tissue composition in metastatic versus non-metastatic tumors.
In particular primary tumors with metastatic potential display a high stromal content and low influx of cytotoxic T cells, which may serve as predictive markers for metastasis formation.