# Targeting a Treg deubiquitinase in antitumor immune therapy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $352,184

## Abstract

Project Summary/Abstract
Tumor growth and metastasis, despite an intact immune system, were considered prime evidence of the poor
immunogenicity of tumor cells, but attempts at immunotherapy to increase anti-tumor responses were largely
unsuccessful. A major hurdle in tumor immunotherapy is the immunosuppression mediated by Regulatory T
(Treg) cells, which function to modulate the immune system by suppressing the function of effector T (Teff)
cells. However, current approaches in targeting Treg have only transient efficacy and are highly unspecific.
The development of new ways to control Treg functions is essential to improving tumor immunotherapy, and is
a central goal of this project. Treg suppressive function is mediated by the transcription factor Forkhehgead
Box P3 (FoxP3). Our preliminary data show that the Ubiquitin-specific peptidase 22 (USP22) is required for
FoxP3 expression, suggesting a critical role for USP22 in Treg suppressive function and stability. More
importantly, genetic USP22 suppression specifically in T cells largely diminished Treg suppressive functions
without impairing, but even enhanced the immune response of conventional CD4 and CD8 T cell activation,
indicating that USP22 is an ideal target to specifically inhibit Treg functions to enhance the antitumor immunity.
Indeed, challenging of both WT and mice harboring a USP22 genetic deletion in Tregs (USP22Treg-KO) with
EG7 lymphoma and B16 melanoma showed an increased in anti-tumor response in USP22Treg-KO mice.
Based on these preliminary observations, we hypothesis that USP22 is a novel regulator of Treg suppressive
functions through modulating FoxP3 expression and a potential therapeutic target to boost the antitumor
immunity. This 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 molecular mechanisms by which
USP22 mediates FoxP3 expression. Aim 3 will evaluate the preclinical efficacy of USP22 suppression in
antitumor immunity using both xenograft and spontaneous melanoma models. The studies will provide
fundamental insights to Treg biology and regulation, and a rationale for USP22 targeting in antitumor immune
therapy.

## Key facts

- **NIH application ID:** 10197845
- **Project number:** 5R01CA232347-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Deyu Fang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,184
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197845

## Citation

> US National Institutes of Health, RePORTER application 10197845, Targeting a Treg deubiquitinase in antitumor immune therapy (5R01CA232347-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197845. Licensed CC0.

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