Targeting a Treg deubiquitinase in antitumor immune therapy

项目总结/摘要 尽管免疫系统完好无损，但肿瘤的生长和转移被认为是穷人的主要证据。 肿瘤细胞的免疫原性，但免疫治疗，以增加抗肿瘤反应的尝试，在很大程度上， 不成功。肿瘤免疫治疗的一个主要障碍是调节性T细胞介导的免疫抑制 Treg）细胞，其通过抑制效应T（Teff）的功能来调节免疫系统。 细胞然而，目前靶向Treg的方法仅具有短暂的功效并且是高度非特异性的。 控制Treg功能的新方法的开发对于改善肿瘤免疫疗法是必不可少的， 这个项目的核心目标。Treg抑制功能由转录因子Forkhehgead介导 方框P3（FoxP 3）。我们的初步数据表明，泛素特异性肽酶22（USP 22）是必需的， FoxP 3表达，表明USP 22在Treg抑制功能和稳定性中的关键作用。更 重要的是，在T细胞中特异性的遗传性USP 22抑制极大地削弱了Treg抑制功能 不损害，甚至增强了常规CD 4和CD 8 T细胞活化的免疫应答， 表明USP 22是特异性抑制Treg功能以增强抗肿瘤免疫的理想靶点。 事实上，用以下方法挑战WT和Treg 2中携带USP 22基因缺失的小鼠（USP 22 Treg-KO）， EG 7淋巴瘤和B16黑色素瘤在USP 22 Treg-KO小鼠中显示出抗肿瘤应答增加。 基于这些初步观察，我们假设USP 22是Treg抑制性调节因子， 通过调节FoxP 3表达和潜在的治疗靶点来增强抗肿瘤作用， 免疫力这一假设将在三个目标中得到解决。目标1将重点研究USP 22在以下方面的作用： 维持Treg抑制功能。目标2将确定特定的分子机制， USP 22介导FoxP 3表达。目的3将评价USP 22抑制在以下患者中的临床前疗效： 使用异种移植物和自发性黑素瘤模型的抗肿瘤免疫。这些研究将提供 Treg生物学和调控的基本见解，以及USP 22在抗肿瘤免疫中的靶向原理 疗法

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.