The Molecular Underpinnings of Treg Plasticity in Cancer

Abstract

Abstract Colorectal cancer (CRC) is one of the most common cancers in the world, yet it remains one of the most difficult to treat. Immunotherapy of CRC using checkpoint inhibitors is only efficacious in approximately 4% of patients with high microsatellite instability (MSI-H). In earlier studies we showed that in patients with inflammatory bowel diseases (IBD) and CRC as well as in the APC Δ468murine polyposis model, Tregs overexpress β-catenin. Furthermore, we demonstrated that expression of a dominant active β-catenin in Tregs induces RORγt, compromising suppressive activity and promoting T H17-like properties. This results in a scurfy-like phenotype. By contrast loss of TCF-1 upregulated RORγt, but only compromised Treg anti-inflammatory functions. These observations suggested cooperation of β-catenin and TCF-1 in regulating Treg plasticity. We show here that in healthy mice, β-catenin expression is significantly higher in Tregs as compared to conventional CD4 +T-cells. In Tregs that express a dominant active β-catenin, ablation of TCF-1 or HEB provide partial rescue, while ablation of both TCF-1 and HEB recovers Treg numbers and prevents the scurfy-like phenotype. These observations suggest that TCF-1, HEB and β-catenin cooperate to determine Treg functions. In search for additional partners, we show that loss of TCF-1 upregulates SATB-1, a chromatin modifier that is known to determine T-cell development and function. Upregulation of SATB-1 is enhanced with the loss of both TCF-1 and HEB. All three transcription factors upregulate RORγt suggesting that they cooperatively determine Treg function and plasticity. Elucidating this cooperation will enhance our ability to control Treg plasticity in health and disease. NIH/NIAID - R01 AI108682-0A1