USP22 stabilizes FoxP3 to maintain Regulatory T cell function through a dual mechanism resulting in tumor immune evasion

Abstract Aggressive cancers are less sensitive to standard cancer treatments available, reducing overall survival rates and increasing relapse percentage in cancer patients. As a result, there is an increasing need for alternative therapeutics that will prolong the survival of patients. Within the last decade, methods to attenuate tumor immune evasion have become a centerpiece of tumor therapies. However, a major hurdle in tumor immunotherapy is the immunosuppression mediated by Regulatory T (Treg) cells, which can promote tumor progression through the suppression of tumor immune evasion. Therefore, the ability to modulate Treg function in the context of cancer could lead to more effective therapies. Here, we identify the ubiquitin-specific peptidase 22 (USP22), a member of the deubiquitination module of the SAGA chromatin modifying complex, as a specific regulator of Foxp3, the lineage-specifying transcription factor of Tregs. Treg-specific ablation of Usp22 in mice reduced Foxp3 at both the transcriptional and post-translational level, creating defects in their suppressive function and leading to spontaneous autoimmunity. Importantly, USP22 ablation protected against tumor growth in multiple cancer models. Collectively, our findings reveal a previously underappreciated physiological function of USP22 in maintaining Treg stability and identify USP22 as a potential target for cancer immunotherapy.