Regulatory T cells (Tregs) are a special type of immune cell with the remarkable ability to suppress excessive inflammation. This makes them promising candidates in adoptive cell therapies – ‘living drugs’ for treating autoimmune diseases, chronic inflammatory conditions, and transplant rejection. However, a major challenge in Treg-based therapies is ensuring these cells remain functional after being expanded in the lab to generate therapeutic products and transfer into patients. The EpiTune project set out to address this issue from a new molecular angle, by investigating how epigenetic mechanisms—chromatin switches that regulate gene activity—affect Treg function and stability.
Our research identified key epigenetic changes that occur during Treg product manufacturing, which can compromise their therapeutic effectiveness. One major discovery was that epigenetic stabilizer elements - regions of the genome essential for Treg identity—undergo modifications over time, reducing their function. We also found that heterochromatin, an inactivated part of the genome, loses important regulatory marks during cell expansion. This destabilization can lead to harmful gene activation and limit the long-term effectiveness of Treg therapies.
To counteract these effects, we developed a CRISPR-based epigenetic editing tool that allows us to precisely modify genetic regulatory elements and restore lost function. By refining our technique, we successfully reprogrammed pro-inflammatory T cells into functional, immunosuppressive Tregs - essentially generating Tregs ‘from scratch’. This breakthrough could significantly expand the number of patients who can benefit from Treg therapy, including those who lack a natural population of functional Tregs. Additionally, this technology holds promise for converting harmful autoreactive immune cells into regulatory cells, opening up new possibilities for personalized medicine.
In parallel, we also tackled the loss of epigenomic stability during cell manufacturing. We uncovered the molecular cause behind this phenomenon and developed a pharmacological intervention approach to preserve the epigenetic identity of Tregs during expansion. This method not only improved Treg functionality but has potential applications in other cell therapies, including cancer immunotherapies and regenerative medicine.
The impact of these findings is already being recognized: our host institution has initiated patent applications to secure intellectual property rights, ensuring these technologies can be translated into real-world treatments. With our discoveries, we are paving the way for more effective, stable, and accessible cell-based therapies - bringing us closer to harnessing the full potential of Tregs in medicine.
