Foxp3-specific Deubiquitinase Modules enhance Treg fitness

Montauti, Elena

doi:https://doi.org/10.21985/n2-d3ds-6j24

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Foxp3-specific Deubiquitinase Modules enhance Treg fitness

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Regulatory T (Treg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumor immunity. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties, can promote autoimmunity and/or facilitate more effective tumor immunity. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. In collaboration with the Marson Lab at UCSF, my thesis identifies several modulators of Foxp3 expression, using a CRISPR-based pooled screening platform for phenotypes in primary mouse Treg cells including ubiquitin-specific peptidase 22 (Usp22). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumor growth in multiple cancer models. These results reveal previously unknown modulator of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.The highly immunosuppressive tumor microenvironment (TME) favors T regulatory (Treg) cell stability and function, while diminishing the anti-tumor activity of effector T cells. Here, we characterized previously unknown TME-specific cellular and molecular mechanisms that promote intratumoral Treg adaptation through Foxp3. We uncovered the critical role of FOXP3-targeting deubiquitinases, ubiquitin specific peptidase 22 (Usp22) and 21 (Usp21) in Treg stabilization under TME-specific environmental stressors including TGF-beta, hypoxia, and nutrient deprivation. Specifically, Usp22 and Usp21 maintain optimal Foxp3 expression in response to alterations in HIF, AMPK and mTOR activity. The simultaneous loss of both USPs synergizes to alter Treg metabolic signatures and impair suppressive mechanisms, resulting in enhanced anti-tumor activity. Finally, we developed the first Usp22-specific small molecule inhibitor, which significantly reduced intratumoral Treg cells and consequently enhanced anti-tumor immunity. My thesis unveils new mechanisms underlying the functional uniqueness of intratumoral Treg cells, and identify Usp22 as an antitumor therapeutic target that inhibits Treg adaptability in the TME.

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