Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy

YAP 在 Treg 功能中的作用和 YAP 靶向癌症免疫治疗

基本信息

批准号：
10547779
负责人：
DREW M. PARDOLL
金额：
$ 36.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547779
关键词：
Activin Receptor Activins Antibodies Biochemical Bioinformatics CD8B1 gene Cancer Patient Cancer Vaccines Cell Differentiation process Cell physiology Cells Cellular biology Chemicals Clinic Cytotoxic T-Lymphocytes Detection Development Effectiveness Elements Evaluation FOXP3 gene Gene Expression Genes Genetic Homeostasis IL2RA gene Immune Immune Tolerance Immune mediated destruction Immune response Immunomodulators Immunosuppression Immunotherapeutic agent Immunotherapy Impairment Implant In Vitro Inflammatory Knockout Mice Malignant Neoplasms Mediating Methodology Modeling Molecular Molecular Biology Mus Pathogenicity Pathology Pathway interactions Patients Pharmaceutical Preparations Physiological Play Protein Deficiency Proteins Quantitative Reverse Transcriptase PCR Regulation Regulatory T-Lymphocyte Research Role Signal Pathway Signal Transduction Stress T cell differentiation T cell response T-Lymphocyte Testing Therapeutic Therapeutic Agents Transforming Growth Factor beta Tumor Antigens Tumor Burden Tumor Escape Tumor Immunity Up-Regulation Verteporfin antagonist anti-PD-1 anti-cancer anti-tumor immune response antitumor effect cancer immunotherapy cofactor experimental study fighting fitness gene function immune activation immune checkpoint blockade immune modulating agents immunoregulation improved in vitro activity in vivo inhibitor insight melanoma neoplasm immunotherapy neoplastic cell neutralizing antibody new therapeutic target novel novel strategies pharmacologic prevent protein expression stem success targeted agent therapeutic target transcription factor transcriptome sequencing tumor tumor eradication tumor growth tumor microenvironment

项目摘要

Background: Foxp3+CD4+CD25+ regulatory T cells (Treg)-mediated immune suppression is crucial for immune evasion by tumor cells and an obstacle for successful tumor immunotherapy. Hence, the ability to disrupt Treg function is of major therapeutic significance. Although Foxp3 is a master regulator of Treg, Foxp3 expression is not sufficient to account for the suppressive capacity of Tregs. It has been suggested that Foxp3 needs to associate with other co-factors in order to suppress non-Treg (T effector) genes and enforce Treg associated gene expression and function. Recently, we found that Yes-associated protein (YAP), a downstream co-activator of the Hippo pathway, is highly expressed by Tregs and is critical for Foxp3-mediated suppressive activity. Furthermore, T cell specific YAP knockout mice mount superior immune responses to implanted B16 melanomas. We hypothesize that YAP is an attractive target for immunotherapeutic strategies aimed at breaking tolerance and enhancing anti-tumor immunity in the cancer setting. Specific Aims: In the current proposal, we are seeking to: 1) Further dissect the molecular mechanisms by which YAP facilitates Foxp3+ Treg function; 2) Understand the consequences of YAP deletion for Treg cell differentiation and function; and 3) Explore the anti-tumor efficacy of YAP inhibitor(s) alone or in combination with immune checkpoint blockade. Objectives & Significance: These studies will expand our understanding of the mechanisms behind YAP facilitates Foxp3 regulation and Treg function. In so doing we will further dissect the molecular mechanism by which YAP facilitates Foxp3-mediated Treg function. Furthermore, we will explore Yap as a potential novel therapeutic target by pharmacologically manipulating YAP activity, and testing various inhibitors for efficacy as breakers of immune tolerance, which is a major obstacle for anti-cancer immunotherapy. The use of such Yap inhibitors in combination with other immune modulators such as anti-PD-1 is expected to improve the effectiveness of immunotherapy, and boost anti-tumor immunity and patient survival. Methodology: In these studies we will deploy biochemical, molecular biology, genetic and bioinformatic approaches to further dissect the role of YAP in Treg cell biology, and attempt to discover known and novel inhibitors of Yap that are effective alone and synergistic with immunotherapies in reducing tumor burden. Both novel and known YAP inhibitors will be tested for their capacity to undermine Treg function and break immune tolerance in vitro and in vivo. Expected Results & Implications: Our experiments will reveal a novel role of YAP in Treg cell function. We predict that a detailed understanding of the physiological role of YAP induction and its impact on Foxp3 and Treg function will provide insight into therapeutic targeting of this pathway. The use of YAP inhibitors in combination with proven checkpoint targeting agents may yield even better anti-tumor efficacy.

背景：FOXP3+CD4+CD25+调节T细胞（TREG）介导的免疫抑制至关重要肿瘤细胞免疫逃避和成功的肿瘤免疫疗法的障碍。因此，能力破坏Treg功能具有主要的治疗意义。虽然Foxp3是Treg的主要监管机构Foxp3 表达不足以说明Treg的抑制能力。有人建议foxp3 需要与其他共同因素关联以抑制非Treg（T效应）基因并强制执行Treg 相关的基因表达和功能。最近，我们发现与是相关的蛋白（YAP），A 河马途径的下游共激活器，由Tregs高度表达，对于FoxP3介导的至关重要抑制活动。此外，T细胞特异性YAP基因敲除小鼠将上级免疫反应安装到植入B16黑色素瘤。我们假设YAP是免疫治疗的有吸引力的目标旨在破坏癌症环境中耐受性并增强抗肿瘤免疫力的策略。具体目的：在当前提案中，我们正在寻求：1）进一步剖析分子机制 yap促进了foxp3+ treg函数； 2）了解YAP缺失对Treg单元的后果分化和功能； 3）单独或组合探索YAP抑制剂的抗肿瘤功效免疫检查点封锁。目标和意义：这些研究将扩大我们对YAP背后机制的理解促进FOXP3调节和Treg功能。这样我们将通过 yap促进了FOXP3介导的Treg功能。此外，我们将探索YAP作为潜在的小说通过在药理学操纵YAP活性的情况下进行治疗靶标，并测试各种抑制剂以促进免疫耐受性的破坏者，这是抗癌免疫疗法的主要障碍。使用这种YAP 预计抑制剂与其他免疫调节剂（例如抗PD-1）结合使用将改善免疫疗法的有效性，并提高抗肿瘤免疫和患者生存。方法论：在这些研究中，我们将部署生化，分子生物学，遗传和生化进一步剖析YAP在Treg细胞生物学中的作用的方法，并试图发现已知和新颖的 YAP的抑制剂是单独有效且与免疫疗法协同减轻肿瘤负担的协同作用。两个都新颖和已知的YAP抑制剂将测试其破坏Treg功能和破坏免疫力的能力体外和体内耐受性。预期结果和含义：我们的实验将揭示YAP在Treg细胞功能中的新作用。我们预测，详细了解YAP诱导的生理作用及其对Foxp3和Foxp3和的影响 TREG功能将提供有关该途径治疗靶向的洞察力。在与经过验证的检查点靶向剂的结合可能会产生更好的抗肿瘤功效。