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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：癌症是死亡的主要原因，并为减少其发病率以及在化学疗法和/或放射后的复发而努力，医生和科学家反复试图提高癌症的免疫原性，以促进宿主抗癌抗癌药物。这些努力在很大程度上没有成功。可能部分是由于宿主FOXP3+ T调节（Treg）细胞在限制抗肿瘤免疫调查中的作用。因此，如果可以逐步完成TREG功能的能力，并且没有全面耗竭的Treg，则可以具有很大的治疗意义，而Tregs对维持免疫稳态至关重要，并且可以预防自身免疫性。去泛素酶（DUB）反转了泛素化的作用，从而稳定了各种蛋白质的表达，这些蛋白质通常通过蛋白质组降解。各种DUB对免疫反应的遗传或药理靶向的影响在很大程度上未知。使用一种新颖的筛查方法，我们开发了遗传和药理数据，指出了DUB，USP7的关键作用，在体外和体内控制鼠Treg抑制，而没有抑制受保护的T细胞反应。我们建议使用遗传和药物方法来确定USP7抑制作用在肺癌的鼠模型中的影响。特别是，我们在免疫能力宿主方面的研究将评估USP7靶向的靶向treg功能并允许宿主免疫调查剂现在限制肿瘤的生长和扩散。我们的研究可能会对恶性肿瘤患者的免疫疗法的新策略产生重大影响，并且可能与艾滋病毒或其他慢性感染患者的管理有关。