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：
10330418
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/10330418
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 Light Malignant Neoplasms Mediating Methodology Modeling Molecular Molecular Biology Mus Pathogenicity Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physiological Play Protein Deficiency Proteins Quantitative Reverse Transcriptase PCR Regulation Regulatory T-Lymphocyte Research Role Signal Pathway Signal Transduction Stress 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 immunotherapeutics cancer immunotherapy experimental study fighting fitness gene function immune activation immune checkpoint blockade immunoregulation improved in vitro activity in vivo inhibitor insight melanoma neoplasm immunotherapy neoplastic cell neutralizing antibody new therapeutic target novel novel strategies 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+调节性T细胞（Treg）介导的免疫抑制对于肿瘤细胞的免疫逃避是成功肿瘤免疫治疗的障碍。因此，能够破坏Treg功能具有重要的治疗意义。尽管 Foxp3 是 Treg 的主要调节因子，但 Foxp3 表达不足以解释 Tregs 的抑制能力。有人建议 Foxp3 需要与其他辅助因子结合才能抑制非 Treg（T 效应子）基因并强化 Treg 相关基因的表达和功能。最近，我们发现Yes相关蛋白（YAP） Hippo 通路的下游共激活因子，由 Tregs 高表达，对于 Foxp3 介导的过程至关重要抑制活动。此外，T 细胞特异性 YAP 敲除小鼠对植入 B16 黑色素瘤。我们假设 YAP 是免疫治疗的一个有吸引力的靶标旨在打破癌症耐受性并增强抗肿瘤免疫力的策略。具体目标：在当前的提案中，我们寻求：1）通过以下方式进一步剖析分子机制：其中YAP促进Foxp3+ Treg功能； 2) 了解YAP缺失对Treg细胞的影响分化和功能； 3) 探索YAP抑制剂单独或联合使用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。在此过程中，我们将进一步剖析分子机制 YAP 促进 Foxp3 介导的 Treg 功能。此外，我们将探索 Yap 作为一本潜在的小说通过药理学操纵 YAP 活性并测试各种抑制剂的功效来确定治疗靶点免疫耐受的破坏者，这是抗癌免疫治疗的主要障碍。使用这样的邑抑制剂与其他免疫调节剂（例如抗 PD-1）组合有望改善免疫疗法的有效性，并提高抗肿瘤免疫力和患者生存率。方法：在这些研究中，我们将采用生物化学、分子生物学、遗传和生物信息学进一步剖析 YAP 在 Treg 细胞生物学中的作用的方法，并尝试发现已知的和新颖的 Yap 抑制剂单独有效，并与免疫疗法协同减少肿瘤负荷。两个都将测试新型和已知的 YAP 抑制剂破坏 Treg 功能和破坏免疫的能力体外和体内耐受性。预期结果和意义：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 Treg 功能将有助于深入了解该通路的治疗靶向。 YAP抑制剂的应用与经过验证的检查点靶向药物组合可能会产生更好的抗肿瘤功效。