# The function of Ubiquitin-Specific Peptidase 22 (USP22) on T regulatory cell function

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2020 · $40,176

## Abstract

Project Summary/Abstract
 Metastatic melanoma is a highly aggressive cancer, making it difficult to target via classical cancer
therapies. Immunotherapy represents a quickly emerging strategy for targeting aggressive cancers, however a
major hurdle is the immunosuppressive environment within the melanoma tumor mediated by Regulatory T
cells (Tregs). Current Treg targeting approaches are non-specific and have only transient efficiency, therefore
the development of new therapies to control Treg function are critical for immunotherapy. Treg suppressive
function is mediated by the transcription factor Forkhead Box P3 (FoxP3), also a specific marker for the Treg
cell line. Our preliminary data show that the Ubiquitin-specific peptidase 22 (USP22) is required for proper
FoxP3 expression, suggesting a critical role for USP22 in Treg suppressive function and stability. The long
term goal of this project is to understand the function of USP22 on Treg suppressive function in the context of
cancer.
 Our lab generated the first conditional knockout mouse model of USP22, and preliminary data show a
dramatic decrease of FoxP3 expression upon USP22 deletion as well as chronic activation of CD4+ and CD8+
T cells. Importantly, a deletion of USP22 in all T cells showed no defect in T effector cell activation, indicating
USP22 as an ideal therapeutic target for modulating immunosuppression within the tumor microenvironment.
Challenging of both WT and mice harboring a USP22 genetic deletion in Tregs (USP22Treg-KO) with EG7
lymphoma showed an increased in anti-tumor response in the USP22Treg-KO background. The function of
USP22 on Tregs in the context of melanoma, a more aggressive cancer, has never been studied.
 Based on the data obtained, the central hypothesis for this study is that USP22 is critical for Treg
stabilization and immunosuppression and that genetic USP22 suppression enhances melanoma antitumor
immunity in mice. The hypothesis will be addressed in three aims. Aim 1 will focus on studying the role of
USP22 on maintaining Treg suppressive function. Aim 2 will determine the specific mechanisms by which
USP22 mediates FoxP3 expression. Aim 3 will address the role of USP22 on Treg function in the context of
melanoma. The methods that will be used to accomplish the proposed aims will include novel transgenic
mouse models, tumor models, as well as biochemistry, molecular, and immunological techniques. The studies
will provide fundamental insights to Treg biology and regulation, and the function of USP22 on immune
suppression and cancer.

## Key facts

- **NIH application ID:** 9868282
- **Project number:** 5F31CA220801-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elena Montauti
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,176
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868282

## Citation

> US National Institutes of Health, RePORTER application 9868282, The function of Ubiquitin-Specific Peptidase 22 (USP22) on T regulatory cell function (5F31CA220801-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868282. Licensed CC0.

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