INHIBITION OF A TREG DEUBIQUITINASE, USP7, PROMOTES ANTI-TUMOR IMMUNITY

抑制 TREG 去泛素酶 (USP7) 可促进抗肿瘤免疫

• 批准号: 8884257
• 负责人: Wayne William Hancock
• 金额: $ 39.76万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884257
• 关键词: Acetylation; Acetyltransferase; Adoptive Cell Transfers; Antigen Receptors; Antitumor Response; Attention; Autoimmunity; Autologous; Cancer Etiology; Cancer Model; Cause of Death; Cell Cycle Progression; Cell physiology; Cells; Cessation of life; Chromatin; Chronic; Clinical Research; Data; Deacetylation; Defect; Deubiquitinating Enzyme; Deubiquitination; Development; EP300 gene; Early Diagnosis; Effector Cell; Enzymes; Fingers; Gene Expression; Genetic; Goals; Growth; HIV; HTATIP gene; Histones; Homeostasis; Human; Immune; Immune response; Immune system; Immunocompetent; Immunotherapy; In Vitro; Incidence; Individual; Infection; Infiltration; Inflammation; Lead; Lysine; MDM2 gene; MLLT7 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Mus; Neoplasm Metastasis; Neurodegenerative Disorders; Non-Histone Chromosomal Proteins; PTEN gene; Patients; Physicians; Physiological; Play; Post-Translational Protein Processing; Prevention; Process; Production; Prognostic Marker; Protein p53; Proteins; Radiation; Recurrence; Regulation; Regulatory T-Lymphocyte; Research; Reservations; Role; Scientist; Signal Transduction; Solid Neoplasm; Staging; Survival Rate; T cell response; T-Lymphocyte; Tail; Testing; Therapeutic; Toxic effect; Transgenes; Tumor Immunity; Ubiquitination; Vaccination; Virus Diseases; base; cell growth; chemotherapy; genetic manipulation; genetic regulatory protein; immunogenicity; improved; in vivo; inhibitor/antagonist; innovation; mortality; multicatalytic endopeptidase complex; mutant; neoplasm immunotherapy; neoplastic cell; novel; p65; premature; prevent; public health relevance; response; screening; translational study; tumor; tumor growth; tumor immunology; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Cancers are a leading cause of death and in efforts to reduce their incidence, as well as their recurrence after chemotherapy and/or radiation, physicians and scientists have repeatedly sought to increase the immunogenicity of cancers so as to promote host anti-cancer immune responses. These efforts were largely unsuccessful; likely in part because of the role of host Foxp3+ T regulatory (Treg) cells in limiting anti-tumor immune responses. Hence, the ability to decrease Treg function may be of major therapeutic significance if this can be done incrementally, and without full-scale depletion of Tregs that are essential to the maintenance of immune homeostasis and for the prevention of autoimmunity. Deubiquitinase enzymes (DUBs) reverse the effects of ubiquitination and thereby stabilize the expression of various proteins that often are otherwise degraded via the proteasome. The effects of genetic or pharmacologic targeting of various DUBs on immune responses are largely unknown. Using a novel screening approach, we have developed genetic and pharmacologic data that point to a key role for the DUB, USP7, in control of murine Treg suppression in vitro and in vivo, without concomitant suppression of protective T cell responses. With a sharp focus on the translational potential of these findings, we propose to determine the effects of USP7 inhibition in murine models of lung cancer, using genetic and pharmacologic approaches. In particular, our studies in immunocompetent hosts will assess whether USP7 targeting can dampen Treg functions and allow host immune responses to now limit the growth and spread of tumors. Our studies could have major consequences for the development of new strategies for immunotherapy in patients with malignancies, and may also have relevance to the management of patients with HIV or other chronic infections.

 描述（由申请人提供）：癌症是导致死亡的主要原因，为了降低其发病率以及化疗和/或放疗后的复发率，医生和科学家反复寻求增加癌症的免疫原性，以促进宿主抗癌免疫应答。这些努力在很大程度上是不成功的;可能部分是因为宿主Foxp 3 + T调节（Treg）细胞在限制抗肿瘤免疫应答中的作用。因此，降低Treg功能的能力可能具有重要的治疗意义，如果这可以增量地进行，并且不需要对维持免疫稳态和预防自身免疫至关重要的Tlag的全面消耗。去泛素化酶（DUBs）逆转泛素化的作用，从而稳定各种蛋白质的表达，这些蛋白质通常通过蛋白酶体降解。各种DUB的遗传或药理学靶向对免疫应答的影响在很大程度上是未知的。使用一种新的筛选方法，我们已经开发了遗传和药理学数据，指出DUB，USP 7在体外和体内控制鼠Treg抑制中的关键作用，而不伴随保护性T细胞应答的抑制。随着对这些发现的翻译潜力的关注，我们建议使用遗传学和药理学方法来确定USP 7抑制在肺癌小鼠模型中的作用。特别是，我们在免疫活性宿主中的研究将评估USP 7靶向是否可以抑制Treg功能，并允许宿主免疫反应限制肿瘤的生长和扩散。我们的研究可能对恶性肿瘤患者免疫治疗新策略的开发产生重大影响，也可能与HIV或其他慢性感染患者的管理相关。