One of the recent advances in cancer treatment is the development of immunotherapy largely through targeting the checkpoint receptors. However, attempts at immunotherapy to increase antitumor immune responses have achieved very limited success. A major hurdle in tumor immunotherapy is mediated by regulatory T (Treg) cells, which suppress the function of antitumor effector T cells. The lineage transcription factor Forkhead Box P3 (FoxP3) is known as a programmer for Treg adaptation in the harsh tumor microenvironment such as metabolic changes and hypoxia. However, the factors that control FoxP3-mediated Treg fitness to orchestrate the survival and functions of intratumoral Treg cells have not been identified. Importantly, our recent publications and preliminary discoveries in the current application suggest that tumor microenvironment factors possibly induce Treg fitness/adaptation through selectively upregulating a deubiquitinase module, including USP21 and USP22, but not USP7, of FoxP3 to control Treg adaptation. The current proposed studies will identify the tumor microenvironment factors that induce USP21 and USP22 expression in Tregs (Aim 1), and to test whether Tregs with simultaneous USP21 and USP22 deletion fail to adapt in the harsh tumor microenvironment, which consequently potentiates the antitumor immune therapy (Aim 2). Results from our proposed study will define a novel molecular cue in control Treg fitness to the tumor microenvironment and provide a rationale for the combined USP21 and USP22 suppression in antitumor immune therapy.
This study identifies a deubiquitination module in controlling Treg adaptation to the harsh tumor microenvironment and provides a rational for simultaneous targeting USP21 and USP22 in antitumor immune therapy.