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

• 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
• 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

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 肿瘤细胞的免疫逃逸是肿瘤免疫治疗成功的障碍。因此，有能力 干扰Treg功能具有重要的治疗意义。虽然Foxp3是Treg的主调节器，但Foxp3 表达不足以解释Tregs的抑制能力。有人认为，Foxp3 需要与其他辅助因子结合才能抑制非Treg(T效应)基因并增强Treg 相关基因的表达和功能。最近，我们发现了YAP，一种 河马途径的下游共激活因子在Tregs中高度表达，并且在Foxp3介导的过程中起关键作用 抑制性活动。此外，T细胞特异性YAP基因敲除小鼠对 植入B16黑色素瘤。我们假设YAP是一个有吸引力的免疫治疗靶点。 旨在打破癌症环境中的耐受性和增强抗肿瘤免疫的战略。 具体目标：在目前的提案中，我们试图：1)通过以下方式进一步剖析分子机制 哪个YAP促进了Foxp3+Treg功能；2)了解YAP缺失对Treg细胞的影响 3)探讨YAP抑制剂S单独或联合应用的抗肿瘤作用 有免疫检查站封锁。 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，我们将通过以下方式进一步剖析分子机制 其中YAP促进了Foxp3介导的Treg功能。此外，我们将探索YAP作为一部潜在的小说 通过药理操作YAP活性并测试各种抑制剂的有效性作为治疗靶点 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YAP 抑制剂与其他免疫调节剂如抗PD-1联合使用有望改善 免疫治疗的有效性，并提高抗肿瘤免疫力和患者的生存。 方法：在这些研究中，我们将运用生化、分子生物学、遗传学和生物信息学 进一步剖析YAP在Treg细胞生物学中的作用，并试图发现已知的和新的 在减轻肿瘤负担方面，YAP的抑制剂单独有效，并与免疫疗法协同作用。两者都有 新的和已知的YAP抑制剂将被测试其破坏Treg功能和破坏免疫的能力 体外和体内耐受性。 预期结果和启示：我们的实验将揭示YAP在Treg细胞功能中的一个新角色。我们 预测对YAP诱导的生理作用及其对Foxp3和Foxp3的影响的详细了解 Treg功能将为这一通路的治疗靶向提供洞察力。YAP抑制剂在临床中的应用 与经过验证的检查点靶向药物相结合，可能会产生更好的抗肿瘤效果。