Targeting a Treg deubiquitinase in antitumor immune therapy

项目摘要/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，但提高抗肿瘤反应的免疫疗法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，其功能是通过抑制效应器T的功能来调节免疫系统。 细胞。然而，目前靶向Treg的方法只有短暂的疗效，而且高度不特异。 控制Treg功能的新方法的开发对于提高肿瘤免疫治疗至关重要，而且 这是该项目的一个核心目标。转录因子Forkhehgead介导Treg抑制功能 方框P3(FoxP3)。我们的初步数据显示，泛素特异性肽酶22(USP22)是 Foxp3的表达，提示USP22在Treg抑制功能和稳定性中起关键作用。更多 重要的是，T细胞中特异的USP22基因抑制大大减弱了Treg抑制功能 而不损害，甚至增强免疫反应的常规的CD4和CD8 T细胞的激活， 提示USP22是特异性抑制Treg功能增强抗肿瘤免疫的理想靶点。 事实上，挑战WT和在Tregs(USP22Treg-KO)中存在USP22基因缺失的小鼠 在USP22Treg-KO小鼠中，EG7淋巴瘤和B16黑色素瘤的抗肿瘤反应增强。 基于这些初步观察，我们假设USP22是Treg抑制的一种新的调节因子 调控FoxP3表达的功能及其增强抗肿瘤作用的潜在靶点 豁免权。这一假设将在三个目标中得到解决。目标1将重点研究USP22在 维持特雷格抑制功能。目标2将确定特定的分子机制， USP22介导FoxP3的表达。目的3将评估USP22抑制的临床前疗效 使用异种移植和自发性黑色素瘤模型的抗肿瘤免疫。这些研究将提供 对Treg生物学和调控的基本见解，以及USP22靶向抗肿瘤免疫的基本原理 心理治疗。

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.