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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+调节性T细胞（Treg）介导的免疫抑制是至关重要的